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  • 1. Amico, Mauro
    et al.
    Finelli, Michele
    Rossi, Ivan
    Zauli, Andrea
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Viklund, Håkan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jones, David
    Krogh, Anders
    Fariselli, Piero
    Luigi Martelli, Pier
    Casadio, Rita
    PONGO: a web server for multiple predictions of all-alpha transmembrane proteins.2006In: Nucleic Acids Res, ISSN 1362-4962, Vol. 34, no Web Server issue, W169-72 p.Article in journal (Refereed)
  • 2. Bano-Polo, Manuel
    et al.
    Martinez-Gill, Luis
    Wallner, Björn
    Nieva, Jose L.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mingarro, Ismael
    Charge Pair Interactions in Transmembrane Helices and Turn Propensity of the Connecting Sequence Promote Helical Hairpin Insertion2013In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 425, no 4, 830-840 p.Article in journal (Refereed)
    Abstract [en]

    alpha-Helical hairpins, consisting of a pair of closely spaced transmembrane (TM) helices that are connected by a short interfacial turn, are the simplest structural motifs found in multi-spanning membrane proteins. In naturally occurring hairpins, the presence of polar residues is common and predicted to complicate membrane insertion. We postulate that the pre-packing process offsets any energetic cost of allocating polar and charged residues within the hydrophobic environment of biological membranes. Consistent with this idea, we provide here experimental evidence demonstrating that helical hairpin insertion into biological membranes can be driven by electrostatic interactions between closely separated, poorly hydrophobic sequences. Additionally, we observe that the integral hairpin can be stabilized by a short loop heavily populated by turn-promoting residues. We conclude that the combined effect of TM-TM electrostatic interactions and tight turns plays an important role in generating the functional architecture of membrane proteins and propose that helical hairpin motifs can be acquired within the context of the Sec61 translocon at the early stages of membrane protein biosynthesis. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains from primary structures.

  • 3.
    Basile, Walter
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Difference in disorder between eukaryotes and prokaryotes is largely due to Serine in linker regionsManuscript (preprint) (Other academic)
    Abstract [en]

    In this study we ask what are the molecular properties that make eukaryotic proteins more disordered than prokaryotic ones. First, we show that on average eukaryotic proteins contain more amino acids that are promoting disorder. In particular the fraction of Serine residues is close to 8% of all residues in eukaryotes and less than 6% in prokaryotes. Second, we show that domains unique to eukaryotes and linker regions in eukaryotes are both more disordered and more abundant than corresponding regions in prokaryotic proteins. Serine is an important residue for post-translational modification and regulatory mechanisms. Therefore, we conclude that it is not unlikely that both the need for regulation in a complex eukaryotic cell and the increased amount of longer multi-domain proteins contribute to the higher intrinsic structural disorder in eukaryotic proteins.

  • 4.
    Basile, Walter
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sachenkova, Oxana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Linköping University, Sweden.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Kungliga Tekniska Högskolan, Sweden.
    High GC content causes orphan proteins to be intrinsically disordered2017In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, no 3, e1005375Article in journal (Refereed)
    Abstract [en]

    De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC) and Drosophila (high GC). GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken.

  • 5.
    Basile, Walter
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Salvatore, Marco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The classification of orphans is improved by combining searches in both proteomes and genomes2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Article in journal (Refereed)
    Abstract [en]

    The detection of genes without homologs (“orphans”) in other species is important, as it provides a glimpse on the evolutionary processes that create novel genes. However, for an unbiased view of such de novo gene creation the detection of these genes needs to be accurate. The estimation of the conservation, and in general the age determination of any gene, is dependent on two factors: (i) a method to detect homologs in a genome and (ii) a set of related genomes. Here, we set out to investigate how the detection of orphans is influenced be these factors. We show that when using multiple genomes and six-frame translations of complete genomes the number of orphans is significantly reduced, when compared with earlier studies. Given these premises we obtain a strict set of 34 orphan Saccharomyces cerevisiae genes, and show that the number of orphans in Drosophila melanogaster and Drosophila pseudoobscura can be reduced to only 30 and 17, respectively.

  • 6.
    Basmarke-Wehelie, Rahma
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jurkowski, Wiktor
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Arnqvist, Anna
    Umea Univ, Dept Med Biochem & Biophys, Sweden.
    Engstrand, Lars
    Karolinska Inst, Swedish Inst Infect Dis Control, Sweden.
    Hagner, Matthias
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Wallin, Elin
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Guan, Na
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Kuranasekera, Hasanthi
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Aro, Helena
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The complement regulator CD46 is bactericidal to Helicobacter pylori and blocks urease activity2011In: Gastroenterology, ISSN 0016-5085, Vol. 141, no 3, 918-928 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer.

    METHODS: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses.

    RESULTS: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice.

    CONCLUSIONS: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection.

  • 7.
    Bendz, Maria
    et al.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Skwark, Marcin
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, Daniel
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Granholm, Viktor
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cristobal, Susana
    Kall, Lukas
    Elofsson, Arne
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane protein shaving with thermolysin can be used to evaluate topology predictors2013In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, no 9, 1467-1480 p.Article in journal (Refereed)
    Abstract [en]

    Topology analysis of membrane proteins can be obtained by enzymatic shaving in combination with MS identification of peptides. Ideally, such analysis could provide quite detailed information about the membrane spanning regions. Here, we examine the ability of some shaving enzymes to provide large-scale analysis of membrane proteome topologies. To compare different shaving enzymes, we first analyzed the detected peptides from two over-expressed proteins. Second, we analyzed the peptides from non-over-expressed Escherichia coli membrane proteins with known structure to evaluate the shaving methods. Finally, the identified peptides were used to test the accuracy of a number of topology predictors. At the end we suggest that the usage of thermolysin, an enzyme working at the natural pH of the cell for membrane shaving, is superior because: (i) we detect a similar number of peptides and proteins using thermolysin and trypsin; (ii) thermolysin shaving can be run at a natural pH and (iii) the incubation time is quite short. (iv) Fewer detected peptides from thermolysin shaving originate from the transmembrane regions. Using thermolysin shaving we can also provide a clear separation between the best and the less accurate topology predictors, indicating that using data from shaving can provide valuable information when developing new topology predictors.

  • 8.
    Bernsel, Andreas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Viklund, Håkan
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Remote homology detection of integral membrane proteins using conserved sequence features2008In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, Vol. 71, no 3, 1387-1399 p.Article in journal (Refereed)
  • 9.
    Bernsel, Andreas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Viklund, Håkan
    Falk, Jenny
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Prediction of membrane-protein topology from first principles2008In: Proceedings of the National Academy of Science of the United States of America, ISSN 0027-8424, Vol. 105, no 20, 7177-7181 p.Article in journal (Refereed)
  • 10.
    Bernsel, Andreas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Viklund, Håkan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hennerdal, Aron
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    TOPCONS: consensus prediction of membrane protein topology2009In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no Suppl. 2, W465-W468 p.Article in journal (Refereed)
    Abstract [en]

    TOPCONS (http://topcons.net/) is a web server for consensus prediction of membrane protein topology. The underlying algorithm combines an arbitrary number of topology predictions into one consensus prediction and quantifies the reliability of the prediction based on the level of agreement between the underlying methods, both on the protein level and on the level of individual TM regions. Benchmarking the method shows that overall performance levels match the best available topology prediction methods, and for sequences with high reliability scores, performance is increased by approximately 10 percentage points. The web interface allows for constraining parts of the sequence to a known inside/outside location, and detailed results are displayed both graphically and in text format.

  • 11.
    Björklund, Asa K
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hedin, Linnea
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Quantitative assessment of the structural bias in protein-protein interaction assays.2008In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 8, no 22, 4657-46667 p.Article in journal (Refereed)
    Abstract [en]

    With recent publications of several large-scale protein-protein interaction (PPI) studies, the realization of the full yeast interaction network is getting closer. Here, we have analysed several yeast protein interaction datasets to understand their strengths and weaknesses. In particular, we investigate the effect of experimental biases on some of the protein properties suggested to be enriched in highly connected proteins. Finally, we use support vector machines (SVM) to assess the contribution of these properties to protein interactivity. We find that protein abundance is the most important factor for detecting interactions in tandem affinity purifications (TAP), while it is of less importance for Yeast Two Hybrid (Y2H) screens. Consequently, sequence conservation and/or essentiality of hubs may be related to their high abundance. Further, proteins with disordered structure are over-represented in Y2H screens and in one, but not the other, large-scale TAP assay. Hence, disordered regions may be important both in transient interactions and interactions in complexes. Finally, a few domain families seem to be responsible for a large part of all interactions. Most importantly, we show that there are method-specific biases in PPI experiments. Thus, care should be taken before drawing strong conclusions based on a single dataset.

  • 12.
    Björklund, Åsa K.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Expansion of Protein Domain Repeats2006In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, no 8, 959-970 p.Article in journal (Refereed)
    Abstract [en]

    Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e. g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

  • 13.
    Björklund, Åsa K.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Frey-Skött, Johannes
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Domain Rearrangements in Protein Evolution2005In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 353, no 4, 911-923 p.Article in journal (Refereed)
    Abstract [en]

    Most eukaryotic proteins are multi-domain proteins that are created from fusions of genes, deletions and internal repetitions. An investigation of such evolutionary events requires a method to find the domain architecture from which each protein originates. Therefore, we defined a novel measure, domain distance, which is calculated as the number of domains that differ between two domain architectures. Using this measure the evolutionary events that distinguish a protein from its closest ancestor have been studied and it was found that indels are more common than internal repetition and that the exchange of a domain is rare. Indels and repetitions are common at both the N and C-terminals while they are rare between domains. The evolution of the majority of multi-domain proteins can be explained by the stepwise insertions of single domains, with the exception of repeats that sometimes are duplicated several domains in tandem. We show that domain distances agree with sequence similarity and semantic similarity based on gene ontology annotations. In addition, we demonstrate the use of the domain distance measure to build evolutionary trees. Finally, the evolution of multi-domain proteins is exemplified by a closer study of the evolution of two protein families, non-receptor tyrosine kinases and RhoGEFs.

  • 14.
    Björklund, Åsa K.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sagit, Rauan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nebulin: A Study of Protein Repeat Evolution2010In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 402, no 1, 38-51 p.Article in journal (Refereed)
    Abstract [en]

    Protein domain repeats are common in proteins that are central to the organization of a cell, in particular in eukaryotes. They are known to evolve through internal tandem duplications. However, the understanding of the underlying mechanisms is incomplete. To shed light on repeat expansion mechanisms, we have studied the evolution of the muscle protein Nebulin, a protein that contains a large number of actin-binding nebulin domains. Nebulin proteins have evolved from an invertebrate precursor containing two nebulin domains. Repeat regions have expanded through duplications of single domains, as well as duplications of a super repeat (SR) consisting of seven nebulins. We show that the SR has evolved independently into large regions in at least three instances: twice in the invertebrate Branchiostoma floridae and once in vertebrates. In-depth analysis reveals several recent tandem duplications in the Nebulin gene. The events involve both single-domain and multidomain SR units or several SR units. There are single events, but frequently the same unit is duplicated multiple times. For instance, an ancestor of human and chimpanzee underwent two tandem duplications. The duplication junction coincides with an Alu transposon, thus suggesting duplication through Alu-mediated homologous recombination. Duplications in the SR region consistently involve multiples of seven domains. However, the exact unit that is duplicated varies both between species and within species. Thus, multiple tandem duplications of the same motif did not create the large Nebulin protein. Finally, analysis of segmental duplications in the human genome reveals that duplications are more common in genes containing domain repeats than in those coding for nonrepeated proteins. In fact, segmental duplications are found three to six times more often in long repeated genes than expected by chance. 

  • 15. Contreras, F.-Xabier
    et al.
    Ernst, Andreas M.
    Haberkant, Per
    Björkholm, Patrik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Gönen, Basak
    Tischer, Christian
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Thiele, Christoph
    Pepperkok, Rainer
    Wieland, Felix
    Brügger, Britta
    Molecular recognition of a single sphingolipid species by a protein’s transmembrane domain2012In: Nature, ISSN 0028-0836, Vol. 481, no 7382, 525-529 p.Article in journal (Refereed)
    Abstract [en]

    Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.

  • 16.
    De Marothy, Minttu T.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Marginally hydrophobic transmembrane alpha-helices shaping membrane protein folding2015In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 24, no 7, 1057-1074 p.Article, review/survey (Refereed)
    Abstract [en]

    Cells have developed an incredible machinery to facilitate the insertion of membrane proteins into the membrane. While we have a fairly good understanding of the mechanism and determinants of membrane integration, more data is needed to understand the insertion of membrane proteins with more complex insertion and folding pathways. This review will focus on marginally hydrophobic transmembrane helices and their influence on membrane protein folding. These weakly hydrophobic transmembrane segments are by themselves not recognized by the translocon and therefore rely on local sequence context for membrane integration. How can such segments reside within the membrane? We will discuss this in the light of features found in the protein itself as well as the environment it resides in. Several characteristics in proteins have been described to influence the insertion of marginally hydrophobic helices. Additionally, the influence of biological membranes is significant. To begin with, the actual cost for having polar groups within the membrane may not be as high as expected; the presence of proteins in the membrane as well as characteristics of some amino acids may enable a transmembrane helix to harbor a charged residue. The lipid environment has also been shown to directly influence the topology as well as membrane boundaries of transmembrane helices-implying a dynamic relationship between membrane proteins and their environment.

  • 17. Dimou, Niki L.
    et al.
    Tsirigos, Konstantinos D.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center, Sweden.
    Bagos, Pantelis G.
    GWAR: robust analysis and meta-analysis of genome-wide association studies2017In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 33, no 10, 1521-1527 p.Article in journal (Refereed)
    Abstract [en]

    Motivation: In the context of genome-wide association studies (GWAS), there is a variety of statistical techniques in order to conduct the analysis, but, in most cases, the underlying genetic model is usually unknown. Under these circumstances, the classical Cochran-Armitage trend test (CATT) is suboptimal. Robust procedures that maximize the power and preserve the nominal type I error rate are preferable. Moreover, performing a meta-analysis using robust procedures is of great interest and has never been addressed in the past. The primary goal of this work is to implement several robust methods for analysis and meta-analysis in the statistical package Stata and subsequently to make the software available to the scientific community. Results: The CATT under a recessive, additive and dominant model of inheritance as well as robust methods based on the Maximum Efficiency Robust Test statistic, the MAX statistic and the MIN2 were implemented in Stata. Concerning MAX and MIN2, we calculated their asymptotic null distributions relying on numerical integration resulting in a great gain in computational time without losing accuracy. All the aforementioned approaches were employed in a fixed or a random effects meta-analysis setting using summary data with weights equal to the reciprocal of the combined cases and controls. Overall, this is the first complete effort to implement procedures for analysis and meta-analysis in GWAS using Stata.

  • 18.
    Ekman, Diana
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Björklund, Åsa K.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Quantification of the Elevated Rate of Domain Rearrangements in Metazoa2007In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 372, no 5, 1337-1348 p.Article in journal (Refereed)
    Abstract [en]

    Most eukaryotic proteins consist of multiple domains created through gene fusions or internal duplications. The most frequent change of a domain architecture (DA) is insertion or deletion of a domain at the N or C terminus. Still, the mechanisms underlying the evolution of multidomain proteins are not very well studied.

    Here, we have studied the evolution of multidomain architectures (MDA), guided by evolutionary information in the form of a phylogenetic tree. Our results show that Pfam domain families and MDAs have been created with comparable rates (0.1–1 per million years (My)). The major changes in DA evolution have occurred in the process of multicellularization and within the metazoan lineage. In contrast, creation of domains seems to have been frequent already in the early evolution. Furthermore, most of the architectures have been created from older domains or architectures, whereas novel domains are mainly found in single-domain proteins. However, a particular group of exon-bordering domains may have contributed to the rapid evolution of novel multidomain proteins in metazoan organisms. Finally, MDAs have evolved predominantly through insertions of domains, whereas domain deletions are less common.

    In conclusion, the rate of creation of multidomain proteins has accelerated in the metazoan lineage, which may partly be explained by the frequent insertion of exon-bordering domains into new architectures. However, our results indicate that other factors have contributed as well.

  • 19.
    Ekman, Diana
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Björklund, Åsa K.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Frey-Skött, Johannes
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Multi-domain Proteins in the Three Kingdoms of Life: Orphan Domains and Other Unassigned Regions2005In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 348, no 1, 241-243 p.Article in journal (Refereed)
    Abstract [en]

    Comparative studies of the proteomes from different organisms have provided valuable information about protein domain distribution in the kingdoms of life. Earlier studies have been limited by the fact that only about 50% of the proteomes could be matched to a domain. Here, we have extended these studies by including less well-defined domain definitions, Pfam-B and clustered domains, MAS, in addition to Pfam-A and SCOP domains. It was found that a significant fraction of these domain families are homologous to Pfam-A or SCOP domains. Further, we show that all regions that do not match a Pfam-A or SCOP domain contain a significantly higher fraction of disordered structure. These unstructured regions may be contained within orphan domains or function as linkers between structured domains. Using several different definitions we have re-estimated the number of multi-domain proteins in different organisms and found that several methods all predict that eukaryotes have approximately 65% multi-domain proteins, while the prokaryotes consist of approximately 40% multi-domain proteins. However, these numbers are strongly dependent on the exact choice of cut-off for domains in unassigned regions. In conclusion, all eukaryotes have similar fractions of multidomain proteins and disorder, whereas a high fraction of repeating domain is distinguished only in multicellular eukaryotes. This implies a role for repeats in cell-cell contacts while the other two features are important for intracellular functions.

  • 20.
    Ekman, Diana
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Identifying and Quantifying Orphan Protein Sequences in Fungi2010In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 396, no 2, 396-405 p.Article in journal (Refereed)
    Abstract [en]

    For large regions of many proteins, and even entire proteins, no homology to known domains or proteins can be detected. These sequences are often referred to as orphans. Surprisingly, it has been reported that the large number of orphans is sustained in spite of a rapid increase of available genomic sequences. However, it is believed that de novo creation of coding sequences is rare in comparison to mechanisms such as domain shuffling and gene duplication; hence, most sequences should have homologs in other genomes. To investigate this, the sequences of 19 complete fungi genomes were compared. By using the phylogenetic relationship between these genomes, we could identify potentially de novo created orphans in Saccharomyces cerevisiae. We found that only a small fraction, <2%, of the S. cerevisiae proteome is orphan, which confirms that de novo creation of coding sequences is indeed rare. Furthermore, we found it necessary to compare the most closely related species to distinguish between de novo created sequences and rapidly evolving sequences where homologs are present but cannot be detected. Next, the orphan proteins (OPs) and orphan domains (ODs) were characterized. First, it was observed that both OPs and ODs are short. In addition, at least some of the OPs have been shown to be functional in experimental assays, showing that they are not pseudogenes. Furthermore, in contrast to what has been reported before and what is seen for older orphans, S. cerevisiae specific ODs and proteins are not more disordered than other proteins. This might indicate that many of the older, and earlier classified, orphans indeed are fast-evolving sequences. Finally, >90% of the detected ODs are located at the protein termini, which suggests that these orphans could have been created by mutations that have affected the start or stop codons.

  • 21.
    Elofsson, Arne
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane protein structure: prediction versus reality.2007In: Annu Rev Biochem, ISSN 0066-4154, Vol. 76, 125-40 p.Article in journal (Refereed)
  • 22.
    Emanuelsson, Olof
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cristóbal, Susana
    In silico prediction of the peroxisomal proteome in fungi, plants and animals.2003In: J Mol Biol, ISSN 0022-2836, Vol. 330, no 2, 443-56 p.Article in journal (Refereed)
  • 23.
    Granseth, Erik
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    A study of the membrane-water interface region of membrane proteins.2005In: J Mol Biol, ISSN 0022-2836, Vol. 346, no 1, 377-85 p.Article in journal (Refereed)
  • 24.
    Hayat, Sikander
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    BOCTOPUS: improved topology prediction of transmembrane β barrel proteins.2012In: Bioinformatics, ISSN 1460-2059, Vol. 28, no 4, 516-522 p.Article in journal (Refereed)
    Abstract [en]

    MOTIVATION: Transmembrane β barrel proteins (TMBs) are found in the outer membrane of Gram-negative bacteria, chloroplast and mitochondria. They play a major role in the translocation machinery, pore formation, membrane anchoring and ion exchange. TMBs are also promising targets for antimicrobial drugs and vaccines. Given the difficulty in membrane protein structure determination, computational methods to identify TMBs and predict the topology of TMBs are important.

    RESULTS: Here, we present BOCTOPUS; an improved method for the topology prediction of TMBs by employing a combination of support vector machines (SVMs) and Hidden Markov Models (HMMs). The SVMs and HMMs account for local and global residue preferences, respectively. Based on a 10-fold cross-validation test, BOCTOPUS performs better than all existing methods, reaching a Q3 accuracy of 87%. Further, BOCTOPUS predicted the correct number of strands for 83% proteins in the dataset. BOCTOPUS might also help in reliable identification of TMBs by using it as an additional filter to methods specialized in this task.

    AVAILABILITY: BOCTOPUS is freely available as a web server at: http://boctopus.cbr.su.se/. The datasets used for training and evaluations are also available from this site.

  • 25.
    Hayat, Sikander
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ranking models of transmembrane beta-barrel proteins using Z-coordinate predictions2012In: Bioinformatics, ISSN 1367-4803, E-ISSN 1460-2059, Vol. 28, no 12, i90-I96 p.Article in journal (Refereed)
    Abstract [en]

    Motivation: Transmembrane beta-barrels exist in the outer membrane of gram-negative bacteria as well as in chloroplast and mitochondria. They are often involved in transport processes and are promising antimicrobial drug targets. Structures of only a few beta-barrel protein families are known. Therefore, a method that could automatically generate such models would be valuable. The symmetrical arrangement of the barrels suggests that an approach based on idealized geometries may be successful. Results: Here, we present tobmodel; a method for generating 3D models of beta-barrel transmembrane proteins. First, alternative topologies are obtained from the BOCTOPUS topology predictor. Thereafter, several 3D models are constructed by using different angles of the beta-sheets. Finally, the best model is selected based on agreement with a novel predictor, ZPRED3, which predicts the distance from the center of the membrane for each residue, i.e. the Z-coordinate. The Z-coordinate prediction has an average error of 1.61 A. Tobmodel predicts the correct topology for 75% of the proteins in the dataset which is a slight improvement over BOCTOPUS alone. More importantly, however, tobmodel provides a C alpha template with an average RMSD of 7.24 A from the native structure.

  • 26. Hayat, Sikander
    et al.
    Peters, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Shu, Nanjiang
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Tsirigos, Konstantinos D.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Inclusion of dyad-repeat pattern improves topology prediction of transmembrane beta-barrel proteins2016In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, no 10, 1571-1573 p.Article in journal (Refereed)
    Abstract [en]

    Accurate topology prediction of transmembrane beta-barrels is still an open question. Here, we present BOCTOPUS2, an improved topology prediction method for transmembrane beta-barrels that can also identify the barrel domain, predict the topology and identify the orientation of residues in transmembrane beta-strands. The major novelty of BOCTOPUS2 is the use of the dyad-repeat pattern of lipid and pore facing residues observed in transmembrane beta-barrels. In a cross-validation test on a benchmark set of 42 proteins, BOCTOPUS2 predicts the correct topology in 69% of the proteins, an improvement of more than 10% over the best earlier method (BOCTOPUS) and in addition, it produces significantly fewer erroneous predictions on non-transmembrane beta-barrel proteins.

  • 27. Hayat, Sikander
    et al.
    Sander, Chris
    Marks, Debora S.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    All-atom 3D structure prediction of transmembrane beta-barrel proteins from sequences2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 17, 5413-5418 p.Article in journal (Refereed)
    Abstract [en]

    Transmembrane beta-barrels (TMBs) carry out major functions in substrate transport and protein biogenesis but experimental determination of their 3D structure is challenging. Encouraged by successful de novo 3D structure prediction of globular and alpha-helical membrane proteins from sequence alignments alone, we developed an approach to predict the 3D structure of TMBs. The approach combines the maximum-entropy evolutionary coupling method for predicting residue contacts (EVfold) with a machine-learning approach (boctopus2) for predicting beta-strands in the barrel. In a blinded test for 19 TMB proteins of known structure that have a sufficient number of diverse homologous sequences available, this combined method (EVfold_bb) predicts hydrogen-bonded residue pairs between adjacent beta-strands at an accuracy of similar to 70%. This accuracy is sufficient for the generation of all-atom 3D models. In the transmembrane barrel region, the average 3D structure accuracy [template-modeling (TM) score] of top-ranked models is 0.54 (ranging from 0.36 to 0.85), with a higher (44%) number of residue pairs in correct strand-strand registration than in earlier methods (18%). Although the nonbarrel regions are predicted less accurately overall, the evolutionary couplings identify some highly constrained loop residues and, for FecA protein, the barrel including the structure of a plug domain can be accurately modeled (TM score = 0.68). Lower prediction accuracy tends to be associated with insufficient sequence information and we therefore expect increasing numbers of beta-barrel families to become accessible to accurate 3D structure prediction as the number of available sequences increases.

  • 28.
    Hedin, Linnea E.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Illergård, Kristoffer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    An Introduction to Membrane Proteins2011In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 10, no 8, 3324-3331 p.Article in journal (Refereed)
    Abstract [en]

    alpha-Helical membrane proteins are important for many biological functions. Due to physicochemical constraints, the structures of membrane proteins differ from the structure of soluble proteins. Historically, membrane protein structures were assumed to be more or less two-dimensional, consisting of long, straight, membrane-spanning parallel helices packed against each other. However, during the past decade, a number of the new membrane protein structures cast doubt on this notion. Today, it is evident that the structures of many membrane proteins are equally complex as for many soluble proteins. Here, we review this development and discuss the consequences for our understanding of membrane protein biogenesis, folding, evolution, and bioinformatics.

  • 29.
    Hedin, Linnea E.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Öjemalm, Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bernsel, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hennerdal, Aron
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Illergård, Kristoffer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Enquist, Karl
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kauko, Anni
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cristobal, Susana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lerch-Bader, Mirjam
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane Insertion of Marginally Hydrophobic Transmembrane Helices Depends on Sequence Context2010In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 396, no 1, 221-229 p.Article in journal (Refereed)
    Abstract [en]

    In mammalian cells, most integral membrane proteins are initially inserted into the endoplasmic reticulum membrane by the so-called Sec61 translocon. However, recent predictions suggest that many transmembrane helices (TMHs) in multispanning membrane proteins are not sufficiently hydrophobic to be recognized as such by the translocon. In this study, we have screened 16 marginally hydrophobic TMHs from membrane proteins of known three-dimensional structure. Indeed, most of these TMHs do not insert efficiently into the endoplasmic reticulum membrane by themselves. To test if loops or TMHs immediately upstream or downstream of a marginally hydrophobic helix might influence the insertion efficiency, insertion of marginally hydrophobic helices was also studied in the presence of their neighboring loops and helices. The results show that flanking loops and nearest-neighbor TMHs are sufficient to ensure the insertion of many marginally hydrophobic helices. However, for at least two of the marginally hydrophobic helices, the local interactions are not enough, indicating that post-insertional rearrangements are involved in the folding of these proteins.

  • 30.
    Hennerdal, Aron
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rapid membrane protein topology prediction2011In: Bioinformatics, ISSN 1367-4803, E-ISSN 1460-2059, Vol. 27, no 9, 1322-1323 p.Article in journal (Refereed)
    Abstract [en]

    State-of-the-art methods for topology of α-helical membrane proteins are based on the use of time-consuming multiple sequence alignments obtained from PSI-BLAST or other sources. Here, we examine if it is possible to use the consensus of topology prediction methods that are based on single sequences to obtain a similar accuracy as the more accurate multiple sequence-based methods. Here, we show that TOPCONS-single performs better than any of the other topology prediction methods tested here, but ~6% worse than the best method that is utilizing multiple sequence alignments. AVAILABILITY AND IMPLEMENTATION: TOPCONS-single is available as a web server from http://single.topcons.net/ and is also included for local installation from the web site. In addition, consensus-based topology predictions for the entire international protein index (IPI) is available from the web server and will be updated at regular intervals.

  • 31.
    Hennerdal, Aron
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Falk, Jenny
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Internal duplications in alpha-helical membrane protein topologies are common but the nonduplicated forms are rare2010In: Protein Science, ISSN 0961-8368, Vol. 19, no 12, 2305-2318 p.Article in journal (Refereed)
    Abstract [en]

    Many alpha-helical membrane proteins contain internal symmetries, indicating that they might have evolved through a gene duplication and fusion event Here, we have characterized internal duplications among membrane proteins of known structure and in three complete genomes We found that the majority of large transmembrane (TM) proteins contain an internal duplication The duplications found showed a large variability both in the number of TM-segments included and in their orientation Surprisingly, an approximately equal number of antiparallel duplications and parallel duplications were found However, of all 11 superfamilies with an internal duplication, only for one, the AcrB Multidrug Efflux Pump, the duplicated unit could be found in its nonduplicated form An evolutionary analysis of the AcrB homologs indicates that several independent fusions have occurred, including the fusion of the SecD and SecF proteins into the 12-TM-protein SecDF in Brucella and Staphylococcus aureus In one additional case, the Vitamin B-12 transporter-like ABC transporters, the protein had undergone an additional fusion to form protein with 20 TM-helices in several bacterial genomes Finally, homologs to all human membrane proteins were used to detect the presence of duplicated and nonduplicated proteins This confirmed that only in rare cases can homologs with different duplication status be found, although internal symmetry is frequent among these proteins One possible explanation is that it is frequent that duplication and fusion events happen simultaneously and that there is almost always a strong selective advantage for the fused form

  • 32. Hughes, Timothy
    et al.
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ardawatia, Himanshu
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Liberles, David A
    Evaluating dosage compensation as a cause of duplicate gene retention in Paramecium tetraurelia.2007In: Genome Biol, ISSN 1465-6914, Vol. 8, no 5, 213- p.Article, review/survey (Other (popular science, discussion, etc.))
  • 33.
    Illergård, Kristoffer
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ardell, David H.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structure is three to ten times more conserved than sequence--a study of structural response in protein cores2009In: Proteins, ISSN 0887-3585, Vol. 77, no 3, 499-508 p.Article in journal (Refereed)
    Abstract [en]

    Protein structures change during evolution in response to mutations. Here, we analyze the mapping between sequence and structure in a set of structurally aligned protein domains. To avoid artifacts, we restricted our attention only to the core components of these structures. We found that on average, using different measures of structural change, protein cores evolve linearly with evolutionary distance (amino acid substitutions per site). This is true irrespective of which measure of structural change we used, whether RMSD or discrete structural descriptors for secondary structure, accessibility, or contacts. This linear response allows us to quantify the claim that structure is more conserved than sequence. Using structural alphabets of similar cardinality to the sequence alphabet, structural cores evolve three to ten times slower than sequences. Although we observed an average linear response, we found a wide variance. Different domain families varied fivefold in structural response to evolution. An attempt to categorically analyze this variance among subgroups by structural and functional category revealed only one statistically significant trend. This trend can be explained by the fact that beta-sheets change faster than alpha-helices, most likely due to that they are shorter and that change occurs at the ends of the secondary structure elements.

  • 34.
    Illergård, Kristoffer
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Callegari, Simone
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    MPRAP: An accessibility predictor for a-helical transmem-brane proteins that performs well inside and outside the membrane2010In: BMC Bioinformatics, ISSN 1471-2105, Vol. 11, 333- p.Article in journal (Refereed)
    Abstract [en]

    Background: In water-soluble proteins it is energetically favorable to bury hydrophobic residues and to expose polar and charged residues. In contrast to water soluble proteins, transmembrane proteins face three distinct environments; a hydrophobic lipid environment inside the membrane, a hydrophilic water environment outside the membrane and an interface region rich in phospholipid head-groups. Therefore, it is energetically favorable for transmembrane proteins to expose different types of residues in the different regions. Results: Investigations of a set of structurally determined transmembrane proteins showed that the composition of solvent exposed residues differs significantly inside and outside the membrane. In contrast, residues buried within the interior of a protein show a much smaller difference. However, in all regions exposed residues are less conserved than buried residues. Further, we found that current state-of-the-art predictors for surface area are optimized for one of the regions and perform badly in the other regions. To circumvent this limitation we developed a new predictor, MPRAP, that performs well in all regions. In addition, MPRAP performs better on complete membrane proteins than a combination of specialized predictors and acceptably on water-soluble proteins. A web-server of MPRAP is available at http://mprap.cbr.su.se/ Conclusion: By including complete a-helical transmembrane proteins in the training MPRAP is able to predict surface accessibility accurately both inside and outside the membrane. This predictor can aid in the prediction of 3D-structure, and in the identification of erroneous protein structures.

  • 35.
    Illergård, Kristoffer
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Callegari, Simone
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    MPRAP: An accessibility predictor for α-helical transmembrane proteinsManuscript (preprint) (Other academic)
    Abstract [en]

    Background:    During the folding of a protein some residues will become exposed to the environmentwhile others will become buried in the protein interior. For water soluble proteins it is en-ergetically favorable to bury hydrophobic residues and expose polar and charged residues tothe surrounding water. However, transmembrane proteins face three distinct environments; ahydrophobic lipid environment inside the membrane, a hydrophilic water environment outsidethe membrane and a interface region rich in phospholipid head-groups. Therefore, for ener-getic reasons the accessible surfaces of transmembrane proteins need to expose different typesof residues at different locations.    Results:    In a set of structurally determined transmembrane proteins it was found that solvent ex-posed residues are quite different inside compared to outside the membrane. In contrast,residues buried within the interior of the protein are much more similar. Further, we foundthat state-of-the-art predictors for surface area are optimized for one of the environments andtherefore perform badly in the other environment. To circumvent this problem we developeda new predictor, MPRAP, that performs well both inside and outside the membrane regions aswell as being better than a combination of specialized predictors. A web-server of MPRAP isavailable at http://mprap.cbr.su.se/    Conclusion:    By including complete α-helical transmembrane proteins in the training we developed apredictor that accurately predicts accessibility both inside and outside the membrane. This pre-dictor can aid in predicting 3D-structure, predicting functional relevance of individual residuesand identification of erroneous protein structures.

  • 36.
    Illergård, Kristoffer
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kauko, Anni
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Polar residues in the membrane core are conserved and directly involved in functionManuscript (preprint) (Other academic)
    Abstract [en]

    Here, we have analyzed strongly polar residues within the membrane core of alpha-helicalmembrane proteins. Although underrepresented, they constitute as much as 9% of all coreresidues and they are found to be more conserved than other core residues. The reason for theconservation is twofold. First, the residues are mainly buried within the proteins and secon-darily they are found to often be directly involved in the function of the protein. Even if mostpolar sidechains are buried, the actual polar groups often border water filled cavities. In addi-tion, polar residues are often directly involved in binding of small compounds in channels andtransporters or long-term interactions with prosthetic groups. The interactions with prostheticgroups in photosynthetic proteins and oxidoreductase proteins are dominated by histidines andflexibility is provided mainly by prolines. It was also predicted that in human membrane pro-teins the polar core residues are overrepresented among active transporter proteins as well asamong GPCRs, while underrepresented in families with few transmembrane regions, such asnon-GPCR receptors. In GPCRs asparagin, histidine and proline residues are overrepresentedwhile in the active transporters prolines and glutamates are most frequent.

  • 37.
    Illergård, Kristoffer
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kauko, Anni
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Why are polar residues within the membrane core evolutionary conserved?2011In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 79, no 1, 79-91 p.Article in journal (Refereed)
    Abstract [en]

    Here, we present a study of polar residues within the membrane core of alpha-helical membrane proteins. As expected, polar residues are less frequent in the membrane than expected. Further, most of these residues are buried within the interior of the protein and are only rarely exposed to lipids. However, the polar groups often border internal water filled cavities, even if the rest of the sidechain is buried. A survey of their functional roles in known structures showed that the polar residues are often directly involved in binding of small compounds, especially in channels and transporters, but other functions including proton transfer, catalysis, and selectivity have also been attributed to these proteins. Among the polar residues histidines often interact with prosthetic groups in photosynthetic-and oxidoreductase-related proteins, whereas pro-lines often are required for conformational changes of the proteins. Indeed, the polar residues in the membrane core are more conserved than other residues in the core, as well as more conserved than polar residues outside the membrane. The reason is twofold; they are often (i) buried in the interior of the protein and (ii) directly involved in the function of the proteins. Finally, a method to identify which polar residues are present within the membrane core directly from protein sequences was developed. Applying the method to the set of all human membrane proteins the prediction indicates that polar residues were most frequent among active transporter proteins and GPCRs, whereas infrequent in families with few transmembrane regions, such as non-GPCR receptors. Proteins 2011; 79: 79-91.

  • 38. Imai, Kenichiro
    et al.
    Hayat, Sikander
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sakiyama, Noriyuki
    Fujita, Naoya
    Tomii, Kentaro
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Horton, Paul
    Localization prediction and structure-based in silico analysis of bacterial proteins: with emphasis on outer membrane proteins.2013In: Data Mining for Systems Biology / [ed] Hiroshi Mamitsuka, Charles DeLisi, Minoru Kanehisa, New York: Humana Press, 2013, Vol. 939, 115-140 p.Chapter in book (Refereed)
    Abstract [en]

    In this chapter, we first discuss protein localization in bacteria and evaluate some localization prediction tools on an independent dataset. Next, we focus on β-barrel outer membrane proteins (BOMPs), describing and evaluating new tools for BOMP detection and topology prediction. Finally, we apply general protein structure prediction methods on these proteins to show that the structure of most BOMPs in E. coli can be modeled reliably.

  • 39.
    Jurkowski, Wiktor
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Yazdi, Samira
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ligand binding properties of human galanin receptors2013In: Molecular membrane biology, ISSN 0968-7688, E-ISSN 1464-5203, Vol. 30, no 2, 206-216 p.Article in journal (Refereed)
    Abstract [en]

    The galanin receptor family comprises of three members, GalR1, GalR2 and GalR3, all belonging to the G-protein-couple receptor superfamily. All three receptors bind the peptide hormone galanin, but show distinctly different binding properties to other molecules and effects on intracellular signaling. To gain insight on the molecular basis of receptor subtype specificity, we have generated a three-dimensional model for each of the galanin receptors based on its homologs in the same family. We found significant differences in the organization of the binding pockets among the three types of receptors, which might be the key for specific molecular recognition of ligands. Through docking of fragments of the galanin peptide and a number of ligands, we investigated the involvement of transmembrane and loop residues in ligand interaction.

  • 40.
    Kauko, Anni
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hedin, Linnea E
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Thebaud, Estelle
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cristobal, Susana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Repositioning of transmembrane alpha-helices during membrane protein folding2010In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 397, no 1, 190-201 p.Article in journal (Refereed)
    Abstract [en]

    We have determined the optimal placement of individual transmembrane helices in the Pyrococcus horikoshii Glt(Ph) glutamate transporter homolog in the membrane. The results are in close agreement with theoretical predictions based on hydrophobicity, but do not, in general, match the known three-dimensional structure, suggesting that transmembrane helices can be repositioned relative to the membrane during folding and oligomerization. Theoretical analysis of a database of membrane protein structures provides additional support for this idea. These observations raise new challenges for the structure prediction of membrane proteins and suggest that the classical two-stage model often used to describe membrane protein folding needs to be modified.

  • 41.
    Kauko, Anni
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Illergård, Kristoffer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Coils in the membrane core are conserved and functionally important2008In: Journal of Molecular Biology, ISSN 0022-2836, Vol. 380, no 1, 170-180 p.Article in journal (Refereed)
    Abstract [en]

    With the increasing number of available α-helical transmembrane (TM) protein structures, the traditional picture of membrane proteins has been challenged. For example, reentrant regions, which enter and exit the membrane at the same side, and interface helices, which lie parallel with the membrane in the membrane–water interface, are common. Furthermore, TM helices are frequently kinked, and their length and tilt angle vary. Here, we systematically analyze 7% of all residues within the deep membrane core that are in coil state. These coils can be found in TM-helix kinks as major breaks in TM helices and as parts of reentrant regions.

    Coil residues are significantly more conserved than other residues. Due to the polar character of the coil backbone, they are either buried or located near aqueous channels. Coil residues are frequently found within channels and transporters, where they introduce the flexibility and polarity required for transport across the membrane. Therefore, we believe that coil residues in the membrane core, while constituting a structural anomaly, are essential for the function of proteins.

  • 42.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Björkholm, Patrik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallner, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Comparison of the efficiency of different protein structure refinement techniques2010Manuscript (preprint) (Other academic)
  • 43.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Skwark, Marcin J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallner, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Assessment of global and local model quality in CASP8 using Pcons and ProQ2009In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 77, no 9, 167-172 p.Article in journal (Refereed)
    Abstract [en]

    Model Quality Assessment Programs (MQAPs) are programs developed to rank protein models. These methods can be trained to predict the overall global quality of a model or what local regions in a model that are likely to be incorrect. In CASP8, we participated with two predictors that predict both global and local quality using either consensus information, Pcons, or purely structural information, ProQ. Consistently with results in previous CASPs, the best performance in CASP8 was obtained using the Pcons method. Furthermore, the results show that the modification introduced into Pcons for CASP8 improved the predictions against GDT_TS and now a correlation coefficient above 0.9 is achieved, whereas the correlation for ProQ is about 0.7. The correlation is better for the easier than for the harder targets, but it is not below 0.5 for a single target and below 0.7 only for three targets. The correlation coefficient for the best local quality MQAP is 0.68 showing that there is still clear room for improvement within this area. We also detect that Pcons still is not always able to identify the best model. However, we show that using a linear combination of Pcons and ProQ it is possible to select models that are better than the models from the best single server. In particular, the average quality over the hard targets increases by about 6% compared with using Pcons alone.

  • 44.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Skwark, Marcin J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallner, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Improved predictions by Pcons.net using multiple templates2011In: Bioinformatics, ISSN 1367-4803, E-ISSN 1460-2059, Vol. 27, no 3, 426-427 p.Article in journal (Refereed)
    Abstract [en]

    Multiple templates can often be used to build more accurate homology models than models built from a single template. Here we introduce PconsM, an automated protocol that uses multiple templates to build protein models. PconsM has been among the top-performing methods in the recent CASP experiments and consistently perform better than the single template models used in Pcons. net. In particular for the easier targets with many alternative templates with a high degree of sequence identity, quality is readily improved with a few percentages over the highest ranked model built on a single template. PconsM is available as an additional pipeline within the Pcons. net protein structure prediction server.

  • 45.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallner, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Using multiple templates to improve quality of homology models in automated homology modeling.2008In: Protein Science, ISSN 0961-8368, Vol. 17, no 6, 990-1002 p.Article in journal (Refereed)
    Abstract [en]

    When researchers build high-quality models of protein structure from sequence homology, it is today common to use several alternative target-template alignments. Several methods can, at least in theory, utilize information from multiple templates, and many examples of improved model quality have been reported. However, to our knowledge, thus far no study has shown that automatic inclusion of multiple alignments is guaranteed to improve models without artifacts. Here, we have carried out a systematic investigation of the potential of multiple templates to improving homology model quality. We have used test sets consisting of targets from both recent CASP experiments and a larger reference set. In addition to Modeller and Nest, a new method (Pfrag) for multiple template-based modeling is used, based on the segment-matching algorithm from Levitt's SegMod program. Our results show that all programs can produce multi-template models better than any of the single-template models, but a large part of the improvement is simply due to extension of the models. Most of the remaining improved cases were produced by Modeller. The most important factor is the existence of high-quality single-sequence input alignments. Because of the existence of models that are worse than any of the top single-template models, the average model quality does not improve significantly. However, by ranking models with a model quality assessment program such as ProQ, the average quality is improved by approximately 5% in the CASP7 test set.

  • 46. Liberles, David A.
    et al.
    Teichmann, Sarah A.
    Bahar, Ivet
    Bastolla, Ugo
    Bloom, Jesse
    Bornberg-Bauer, Erich
    Colwell, Lucy J.
    de Koning, A. P. Jason
    Dokholyan, Nikolay V.
    Echave, Julian
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gerloff, Dietlind L.
    Goldstein, Richard A.
    Grahnen, Johan A.
    Holder, Mark T.
    Lakner, Clemens
    Lartillot, Nicholas
    Lovell, Simon C.
    Naylor, Gavin
    Perica, Tina
    Pollock, David D.
    Pupko, Tal
    Regan, Lynne
    Roger, Andrew
    Rubinstein, Nimrod
    Shakhnovich, Eugene
    Sjoelander, Kimmen
    Sunyaev, Shamil
    Teufel, Ashley I.
    Thorne, Jeffrey L.
    Thornton, Joseph W.
    Weinreich, Daniel M.
    Whelan, Simon
    The interface of protein structure, protein biophysics, and molecular evolution2012In: Protein Science, ISSN 0961-8368, Vol. 21, no 6, 769-785 p.Article, review/survey (Refereed)
    Abstract [en]

    The interface of protein structural biology, protein biophysics, molecular evolution, and molecular population genetics forms the foundations for a mechanistic understanding of many aspects of protein biochemistry. Current efforts in interdisciplinary protein modeling are in their infancy and the state-of-the art of such models is described. Beyond the relationship between amino acid substitution and static protein structure, protein function, and corresponding organismal fitness, other considerations are also discussed. More complex mutational processes such as insertion and deletion and domain rearrangements and even circular permutations should be evaluated. The role of intrinsically disordered proteins is still controversial, but may be increasingly important to consider. Protein geometry and protein dynamics as a deviation from static considerations of protein structure are also important. Protein expression level is known to be a major determinant of evolutionary rate and several considerations including selection at the mRNA level and the role of interaction specificity are discussed. Lastly, the relationship between modeling and needed high-throughput experimental data as well as experimental examination of protein evolution using ancestral sequence resurrection and in vitro biochemistry are presented, towards an aim of ultimately generating better models for biological inference and prediction.

  • 47.
    Light, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Basile, Walter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Orphans and new gene origination, a structural and evolutionary perspective2014In: Current opinion in structural biology, ISSN 0959-440X, E-ISSN 1879-033X, Vol. 26, 73-83 p.Article in journal (Refereed)
    Abstract [en]

    The frequency of de novo creation of proteins has been debated. Early it was assumed that de novo creation should be extremely rare and that the vast majority of all protein coding genes were created in early history of life. However, the early genomics era lead to the insight that protein coding genes do appear to be lineage-specific. Today, with thousands of completely sequenced genomes, this impression remains. It has even been proposed that the creation of novel genes, a continuous process where most de novo genes are short-lived, is as frequent as gene duplications. There exist reports with strongly indicative evidence for de novo gene emergence in many organisms ranging from Bacteria, sometimes generated through bacteriophages, to humans, where orphans appear to be overexpressed in brain and testis. In contrast, research on protein evolution indicates that many very distantly related proteins appear to share partial homology. Here, we discuss recent results on de novo gene emergence, as well as important technical challenges limiting our ability to get a definite answer to the extent of de novo protein creation.

  • 48.
    Light, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    The impact of splicing on protein domain architecture2013In: Current opinion in structural biology, ISSN 0959-440X, E-ISSN 1879-033X, Vol. 23, no 3, 451-458 p.Article in journal (Refereed)
    Abstract [en]

    Many proteins are composed of protein domains, functional units of common descent. Multidomain forms are common in all eukaryotes making up more than half of the proteome and the evolution of novel domain architecture has been accelerated in metazoans. It is also becoming increasingly clear that alternative splicing is prevalent among vertebrates. Given that protein domains are defined as structurally, functionally and evolutionarily distinct units, one may speculate that some alternative splicing events may lead to clean excisions of protein domains, thus generating a number of different domain architectures from one gene template. However, recent findings indicate that smaller alternative splicing events, in particular in disordered regions, might be more prominent than domain architectural changes.The problem of identifying protein isoforms is, however, still not resolved. Clearly, many splice forms identified through detection of mRNA sequences appear to produce 'nonfunctional' proteins, such as proteins with missing internal secondary structure elements. Here, we review the state of the art methods for identification of functional isoforms and present a summary of what is known, thus far, about alternative splicing with regard to protein domain architectures.

  • 49.
    Light, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sagit, Rauan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ekman, Diana
    Karolinska Institute, Sweden.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Long indels are disordered: A study of disorder and indels in homologous eukaryotic proteins2013In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1834, no 5, 890-897 p.Article in journal (Refereed)
    Abstract [en]

    Proteins evolve through point mutations as well as by insertions and deletions (indels). During the last decade it has become apparent that protein regions that do not fold into three-dimensional structures, i.e. intrinsically disordered regions, are quite common. Here, we have studied the relationship between protein disorder and indels using HMM-HMM pairwise alignments in two sets of orthologous eukaryotic protein pairs. First, we show that disordered residues are much more frequent among indel residues than among aligned residues and, also are more prevalent among indels than in coils. Second, we observed that disordered residues are particularly common in longer indels. Disordered indels of short-to-medium size are prevalent in the non-terminal regions of proteins while the longest indels, ordered and disordered alike, occur toward the termini of the proteins where new structural units are comparatively well tolerated. Finally, while disordered regions often evolve faster than ordered regions and disorder is common in indels, there are some previously recognized protein families where the disordered region is more conserved than the ordered region. We find that these rare proteins are often involved in information processes, such as RNA processing and translation. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.

  • 50.
    Light, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sagit, Rauan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ithychanda, Sujay S.
    Qin, Jun
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    The evolution of filamin - A protein domain repeat perspective2012In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 179, no 3, 289-298 p.Article in journal (Refereed)
    Abstract [en]

    Particularly in higher eukaryotes, some protein domains are found in tandem repeats, performing broad functions often related to cellular organization. For instance, the eukaryotic protein filamin interacts with many proteins and is crucial for the cytoskeleton. The functional properties of long repeat domains are governed by the specific properties of each individual domain as well as by the repeat copy number. To provide better understanding of the evolutionary and functional history of repeating domains, we investigated the mode of evolution of the filamin domain in some detail. Among the domains that are common in long repeat proteins, sushi and spectrin domains evolve primarily through cassette tandem duplications while scavenger and immunoglobulin repeats appear to evolve through clustered tandem duplications. Additionally, immunoglobulin and filamin repeats exhibit a unique pattern where every other domain shows high sequence similarity. This pattern may be the result of tandem duplications, serve to avert aggregation between adjacent domains or it is the result of functional constraints. In filamin, our studies confirm the presence of interspersed integrin binding domains in vertebrates, while invertebrates exhibit more varied patterns, including more clustered integrin binding domains. The most notable case is leech filamin, which contains a 20 repeat expansion and exhibits unique dimerization topology. Clearly, invertebrate filamins are varied and contain examples of similar adjacent integrin-binding domains. Given that invertebrate integrin shows more similarity to the weaker filamin binder, integrin beta 3, it is possible that the distance between integrin-binding domains is not as crucial for invertebrate filamins as for vertebrates.

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