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  • 1. Barrio, Alvaro Martinez
    et al.
    Lamichhaney, Sangeet
    Fan, Guangyi
    Rafati, Nima
    Pettersson, Mats
    Zhang, He
    Dainat, Jacques
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hoppner, Marc
    Jern, Patric
    Martin, Marcel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nystedt, Björn
    Liu, Xin
    Chen, Wenbin
    Liang, Xinming
    Shi, Chengcheng
    Fu, Yuanyuan
    Ma, Kailong
    Zhan, Xiao
    Feng, Chungang
    Gustafson, Ulla
    Rubin, Carl-Johan
    Almen, Markus Sallman
    Blass, Martina
    Casini, Michele
    Folkvord, Arild
    Laikre, Linda
    Stockholm University, Faculty of Science, Department of Zoology.
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology.
    Lee, Simon Ming-Yuen
    Xu, Xun
    Andersson, Leif
    The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e12081Article in journal (Refereed)
    Abstract [en]

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

  • 2. Hultqvist, Greta
    et al.
    Åberg, Emma
    Camilloni, Carlo
    Sundell, Gustav N.
    Andersson, Eva
    Dogan, Jakob
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Uppsala University, Sweden.
    Chi, Celestine N.
    Vendruscolo, Michele
    Jemth, Per
    Emergence and evolution of an interaction between intrinsically disordered proteins2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e16059Article in journal (Refereed)
    Abstract [en]

    Protein-protein interactions involving intrinsically disordered proteins are important for cellular function and common in all organisms. However, it is not clear how such interactions emerge and evolve on a molecular level. We performed phylogenetic reconstruction, resurrection and biophysical characterization of two interacting disordered protein domains, CID and NCBD. CID appeared after the divergence of protostomes and deuterostomes 450-600 million years ago, while NCBD was present in the protostome/deuterostome ancestor. The most ancient CID/NCBD formed a relatively weak complex (K(d similar to)5 mu M). At the time of the first vertebrate-specific whole genome duplication, the affinity had increased (K-d\similar to 200 nM) and was maintained in further speciation. Experiments together with molecular modeling using NMR chemical shifts suggest that new interactions involving intrinsically disordered proteins may evolve via a low-affinity complex which is optimized by modulating direct interactions as well as dynamics, while tolerating several potentially disruptive mutations.

  • 3.
    Kimanius, Dari
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Forsberg, Björn O.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Scheres, Sjors H. W.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-22016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e18722Article in journal (Refereed)
    Abstract [en]

    By reaching near-atomic resolution for a wide range of specimens, single-particle cryo-EM structure determination is transforming structural biology. However, the necessary calculations come at large computational costs, which has introduced a bottleneck that is currently limiting throughput and the development of new methods. Here, we present an implementation of the RELION image processing software that uses graphics processors (GPUs) to address the most computationally intensive steps of its cryo-EM structure determination workflow. Both image classification and high-resolution refinement have been accelerated more than an order-of-magnitude, and template-based particle selection has been accelerated well over two orders-of-magnitude on desktop hardware. Memory requirements on GPUs have been reduced to fit widely available hardware, and we show that the use of single precision arithmetic does not adversely affect results. This enables high-resolution cryo-EM structure determination in a matter of days on a single workstation.

  • 4. Koenig, Daniel
    et al.
    Hagmann, Jörg
    Li, Rachel
    Bemm, Felix
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Nueffer, Barbara
    Wright, Stephen
    Weigel, Detlef
    Long-term balancing selection drives evolution of immunity genes in Capsella2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e43606Article in journal (Refereed)
    Abstract [en]

    Genetic drift is expected to remove polymorphism from populations over long periods of time, with the rate of polymorphism loss being accelerated when species experience strong reductions in population size. Adaptive forces that maintain genetic variation in populations, or balancing selection, might counteract this process. To understand the extent to which natural selection can drive the retention of genetic diversity, we document genomic variability after two parallel species-wide bottlenecks in the genus Capsella. We find that ancestral variation preferentially persists at immunity related loci, and that the same collection of alleles has been maintained in different lineages that have been separated for several million years. By reconstructing the evolution of the disease-related locus MLO2b, we find that divergence between ancient haplotypes can be obscured by referenced based re-sequencing methods, and that trans-specific alleles can encode substantially diverged protein sequences. Our data point to long-term balancing selection as an important factor shaping the genetics of immune systems in plants and as the predominant driver of genomic variability after a population bottleneck.

  • 5.
    Kudva, Renuka
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tian, Pengfei
    Pardo-Avila, Fátima
    Carroni, Marta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Best, Robert B.
    Bernstein, Harris D.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    The shape of the bacterial ribosome exit tunnel affects cotranslational protein folding2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e36326Article in journal (Refereed)
    Abstract [en]

    The E. coli ribosome exit tunnel can accommodate small folded proteins, while larger ones fold outside. It remains unclear, however, to what extent the geometry of the tunnel influences protein folding. Here, using E. coli ribosomes with deletions in loops in proteins uL23 and uL24 that protrude into the tunnel, we investigate how tunnel geometry determines where proteins of different sizes fold. We find that a 29-residue zinc-finger domain normally folding close to the uL23 loop folds deeper in the tunnel in uL23 Delta loop ribosomes, while two similar to 100 residue proteins normally folding close to the uL24 loop near the tunnel exit port fold at deeper locations in uL24 Delta loop ribosomes, in good agreement with results obtained by coarse-grained molecular dynamics simulations. This supports the idea that cotranslational folding commences once a protein domain reaches a location in the exit tunnel where there is sufficient space to house the folded structure.

  • 6.
    Masser, Anna E.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kang, Wenjing
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Roy, Joydeep
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Quintana-Cordero, Jany
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Friedländer, Marc R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf12019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e47791Article in journal (Refereed)
    Abstract [en]

    Hsf1 is an ancient transcription factor that responds to protein folding stress by inducing the heat-shock response (HSR) that restore perturbed proteostasis. Hsp70 chaperones negatively regulate the activity of Hsf1 via stress-responsive mechanisms that are poorly understood. Here, we have reconstituted budding yeast Hsf1-Hsp70 activation complexes and find that surplus Hsp70 inhibits Hsf1 DNA-binding activity. Hsp70 binds Hsf1 via its canonical substrate binding domain and Hsp70 regulates Hsf1 DNA-binding activity. During heat shock, Hsp70 is out-titrated by misfolded proteins derived from ongoing translation in the cytosol. Pushing the boundaries of the regulatory system unveils a genetic hyperstress program that is triggered by proteostasis collapse and involves an enlarged Hsf1 regulon. The findings demonstrate how an apparently simple chaperone-titration mechanism produces diversified transcriptional output in response to distinct stress loads.

  • 7.
    Matsuda, Ryo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hosono, Chie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Samakovlis, Christos
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Justus Liebig University of Giessen, Germany.
    Saigo, Kaoru
    Multipotent versus differentiated cell fate selection in the developing Drosophila airways2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e09646Article in journal (Refereed)
    Abstract [en]

    Developmental potentials of cells are tightly controlled at multiple levels. The embryonic Drosophila airway tree is roughly subdivided into two types of cells with distinct developmental potentials: a proximally located group of multipotent adult precursor cells (P-fate) and a distally located population of more differentiated cells (D-fate). We show that the GATA-family transcription factor (TF) Grain promotes the P-fate and the POU-homeobox TF Ventral veinless (Vvl/Drifter/U-turned) stimulates the D-fate. Hedgehog and receptor tyrosine kinase (RTK) signaling cooperate with Vvl to drive the D-fate at the expense of the P-fate while negative regulators of either of these signaling pathways ensure P-fate specification. Local concentrations of Decapentaplegic/BMP, Wingless/Wnt, and Hedgehog signals differentially regulate the expression of D-factors and P-factors to transform an equipotent primordial field into a concentric pattern of radially different morphogenetic potentials, which gradually gives rise to the distal-proximal organization of distinct cell types in the mature airway.

  • 8.
    Mühleip, Alexander
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    McComas, Sarah E.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Amunts, Alexey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Structure of a mitochondrial ATP synthase with bound native cardiolipin2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e51179Article in journal (Refereed)
    Abstract [en]

    The mitochondrial ATP synthase fuels eukaryotic cells with chemical energy. Here we report the cryo-EM structure of a divergent ATP synthase dimer from mitochondria of Euglena gracilis, a member of the phylum Euglenozoa that also includes human parasites. It features 29 different subunits, 8 of which are newly identified. The membrane region was determined to 2.8 angstrom resolution, enabling the identification of 37 associated lipids, including 25 cardiolipins, which provides insight into protein-lipid interactions and their functional roles. The rotor-stator interface comprises four membrane-embedded horizontal helices, including a distinct subunit a. The dimer interface is formed entirely by phylum-specific components, and a peripherally associated subcomplex contributes to the membrane curvature. The central and peripheral stalks directly interact with each other. Last, the ATPase inhibitory factor 1 (IF1) binds in a mode that is different from human, but conserved in Trypanosomatids.

  • 9. Nakane, Takanori
    et al.
    Kimanius, Dari
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Scheres, Sjors H. W.
    Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e36861Article in journal (Refereed)
    Abstract [en]

    Macromolecular complexes that exhibit continuous forms of structural flexibility pose a challenge for many existing tools in cryo-EM single-particle analysis. We describe a new tool, called multi-body refinement, which models flexible complexes as a user-defined number of rigid bodies that move independently from each other. Using separate focused refinements with iteratively improved partial signal subtraction, the new tool generates improved reconstructions for each of the defined bodies in a fully automated manner. Moreover, using principal component analysis on the relative orientations of the bodies over all particle images in the data set, we generate movies that describe the most important motions in the data. Our results on two test cases, a cytoplasmic ribosome from Plasmodium falciparum, and the spliceosomal B-complex from yeast, illustrate how multi-body refinement can be useful to gain unique insights into the structure and dynamics of large and flexible macromolecular complexes.

  • 10. Pei, Sen
    et al.
    Morone, Flaviano
    Liljeros, Fredrik
    Stockholm University, Faculty of Social Sciences, Department of Sociology.
    Makse, Hernán
    Shaman, Jeffrey L.
    Inference and control of the nosocomial transmission of methicillin-resistant Staphylococcus aureus2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e40977Article in journal (Refereed)
    Abstract [en]

    Methicillin-resistant Staphylococcus aureus (MRSA) is a continued threat to human health in both community and healthcare settings. In hospitals, control efforts would benefit from accurate estimation of asymptomatic colonization and infection importation rates from the community. However, developing such estimates remains challenging due to limited observation of colonization and complicated transmission dynamics within hospitals and the community. Here, we develop an inference framework that can estimate these key quantities by combining statistical filtering techniques, an agent-based model, and real-world patient-to-patient contact networks, and use this framework to infer nosocomial transmission and infection importation over an outbreak spanning 6 years in 66 Swedish hospitals. In particular, we identify a small number of patients with disproportionately high risk of colonization. In retrospective control experiments, interventions targeted to these individuals yield a substantial improvement over heuristic strategies informed by number of contacts, length of stay and contact tracing.

  • 11.
    Quin, Jaclyn E.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bujila, Ioana
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chérif, Mariama
    Sanou, Guillaume S.
    Qu, Ying
    Homann, Manijeh Vafa
    Rolicka, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sirima, Sodiomon B.
    O'Connell, Mary A.
    Lennartsson, Andreas
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nebie, Issa
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e29156Article in journal (Refereed)
    Abstract [en]

    The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups. However, the basis for this lower susceptibility to malaria by the Fulani is unknown. The incidence of classic malaria resistance genes are lower in the Fulani than in other sympatric ethnic populations, and targeted SNP analyses of other candidate genes involved in the immune response to malaria have not been able to account for the observed difference in the Fulani susceptibility to P.falciparum. Therefore, we have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P.falciparum malaria. When we compared uninfected and infected Fulani individuals, in contrast to uninfected and infected individuals from the sympatric ethnic group Mossi, we observed a key difference: a strong transcriptional response was only detected in the monocyte fraction of the Fulani, where over 1000 genes were significantly differentially expressed upon P.falciparum infection.

  • 12. Reddy, Hemanth K. N.
    et al.
    Carroni, Marta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hajdu, Janos
    Svenda, Martin
    Electron cryo-microscopy of bacteriophage PR772 reveals the elusive vertex complex and the capsid architecture2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e48496Article in journal (Refereed)
    Abstract [en]

    Bacteriophage PR772, a member of the Tectiviridae family, has a 70 nm diameter icosahedral protein capsid that encapsulates a lipid membrane, dsDNA, and various internal proteins. An icosahedrally averaged CryoEM reconstruction of the wild-type virion and a localized reconstruction of the vertex region reveal the composition and the structure of the vertex complex along with new protein conformations that play a vital role in maintaining the capsid architecture of the virion. The overall resolution of the virion is 2.75 angstrom, while the resolution of the protein capsid is 2.3 angstrom. The conventional penta-symmetron formed by the capsomeres is replaced by a large vertex complex in the pseudo T = 25 capsid. All the vertices contain the host-recognition protein, P5; two of these vertices show the presence of the receptor-binding protein, P2. The 3D structure of the vertex complex shows interactions with the viral membrane, indicating a possible mechanism for viral infection.

  • 13.
    Rozman Grinberg, Inna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hasan, Mahmudul
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Crona, Mikael
    Jonna, Venkateswara Rao
    Loderer, Chrishtoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sahlin, Margareta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Markova, Natalia
    Borovok, Ilya
    Berggren, Gustav
    Hofer, Anders
    Logan, Derek T.
    Sjöberg, Britt-Marie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e31529Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, the ATP-cone, has been found exclusively in the catalytic subunit. In two class I RNR subclasses whose catalytic subunit lacks the ATP-cone, we discovered ATP-cones in the radical-generating subunit. The ATP-cone in the Leeuwenhoekiella blandensis radical-generating subunit regulates activity via quaternary structure induced by binding of nucleotides. ATP induces enzymatically competent dimers, whereas dATP induces non-productive tetramers, resulting in different holoenzymes. The tetramer forms by interactions between ATP-cones, shown by a 2.45 A crystal structure. We also present evidence for an (MnMnIV)-Mn-III metal center. In summary, lack of an ATP-cone domain in the catalytic subunit was compensated by transfer of the domain to the radical-generating subunit. To our knowledge, this represents the first observation of transfer of an allosteric domain between components of the same enzyme complex.

  • 14. Santos, Joana A.
    et al.
    Rempel, Stephan
    Mous, Sandra T. M.
    Pereira, Cristiane T.
    ter Beek, Josy
    de Gier, Jan-Willem
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Guskov, Albert
    Slotboom, Dirk J.
    Functional and structural characterization of an ECF-type ABC transporter for vitamin B122018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e35828Article in journal (Refereed)
    Abstract [en]

    Vitamin B12 (cobalamin) is the most complex B-type vitamin and is synthetized exclusively in a limited number of prokaryotes. Its biologically active variants contain rare organometallic bonds, which are used by enzymes in a variety of central metabolic pathways such as L-methionine synthesis and ribonucleotide reduction. Although its biosynthesis and role as cofactor are well understood, knowledge about uptake of cobalamin by prokaryotic auxotrophs is scarce. Here, we characterize a cobalamin-specific ECF-type ABC transporter from Lactobacillus delbrueckii, ECF-CbrT, and demonstrate that it mediates the specific, ATP-dependent uptake of cobalamin. We solved the crystal structure of ECF-CbrT in an apo conformation to 3.4 angstrom resolution. Comparison with the ECF transporter for folate (ECF-FoIT2) from the same organism, reveals how the identical ECF module adjusts to interact with the different substrate binding proteins FoIT2 and CbrT. ECF-CbrT is unrelated to the well-characterized B12 transporter BtuCDF, but their biochemical features indicate functional convergence.

  • 15. Sapala, Aleksandra
    et al.
    Runions, Adam
    Routier-Kierzkowska, Anne-Lise
    Das Gupta, Mainak
    Hong, Lilan
    Hofhuis, Hugo
    Verger, Stephane
    Mosca, Gabriella
    Li, Chun-Biu
    Stockholm University, Faculty of Science, Department of Mathematics.
    Hay, Angela
    Hamant, Olivier
    Roeder, Adrienne H. K.
    Tsiantis, Miltos
    Prusinkiewicz, Przemyslaw
    Smith, Richard S.
    Why plants make puzzle cells, and how their shape emerges2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e32794Article in journal (Refereed)
    Abstract [en]

    The shape and function of plant cells are often highly interdependent. The puzzle shaped cells that appear in the epidermis of many plants are a striking example of a complex cell shape, however their functional benefit has remained elusive. We propose that these intricate forms provide an effective strategy to reduce mechanical stress in the cell wall of the epidermis. When tissue-level growth is isotropic, we hypothesize that lobes emerge at the cellular level to prevent formation of large isodiametric cells that would bulge under the stress produced by turgor pressure. Data from various plant organs and species support the relationship between lobes and growth isotropy, which we test with mutants where growth direction is perturbed. Using simulation models we show that a mechanism actively regulating cellular stress plausibly reproduces the development of epidermal cell shape. Together, our results suggest that mechanical stress is a key driver of cell-shape morphogenesis.

  • 16. Shanmuganathan, Vivekanandan
    et al.
    Schiller, Nina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Magoulopoulou, Anastasia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cheng, Jingdong
    Braunger, Katharina
    Cymer, Florian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berninghausen, Otto
    Beatrix, Birgitta
    Kohno, Kenji
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Beckmann, Roland
    Structural and mutational analysis of the ribosome-arresting human XBP1u2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e46267Article in journal (Refereed)
    Abstract [en]

    XBP1u, a central component of the unfolded protein response (UPR), is a mammalian protein containing a functionally critical translational arrest peptide (AP). Here, we present a 3 angstrom cryo-EM structure of the stalled human XBP1u AP. It forms a unique turn in the ribosomal exit tunnel proximal to the peptidyl transferase center where it causes a subtle distortion, thereby explaining the temporary translational arrest induced by XBP1u. During ribosomal pausing the hydrophobic region 2 (HR2) of XBP1u is recognized by SRP, but fails to efficiently gate the Sec61 translocon. An exhaustive mutagenesis scan of the XBP1u AP revealed that only 8 out of 20 mutagenized positions are optimal; in the remaining 12 positions, we identify 55 different mutations increase the level of translational arrest. Thus, the wildtype XBP1u AP induces only an intermediate level of translational arrest, allowing efficient targeting by SRP without activating the Sec61 channel.

  • 17. Snapp, Erik Lee
    et al.
    McCaul, Nicholas
    Quandte, Matthias
    Cabartova, Zuzana
    Bontjer, Ilja
    Källgren, Carolina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Land, Aafke
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sanders, Rogier W.
    Braakman, Ineke
    Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e26067Article in journal (Refereed)
    Abstract [en]

    Like all other secretory proteins, the HIV-1 envelope glycoprotein gp160 is targeted to the endoplasmic reticulum (ER) by its signal peptide during synthesis. Proper gp160 folding in the ER requires core glycosylation, disulfide-bond formation and proline isomerization. Signal-peptide cleavage occurs only late after gp160 chain termination and is dependent on folding of the soluble subunit gp120 to a near-native conformation. We here detail the mechanism by which co-translational signal-peptide cleavage is prevented. Conserved residues from the signal peptide and residues downstream of the canonical cleavage site form an extended alpha-helix in the ER membrane, which covers the cleavage site, thus preventing cleavage. A point mutation in the signal peptide breaks the alpha helix allowing co-translational cleavage. We demonstrate that postponed cleavage of gp160 enhances functional folding of the molecule. The change to early cleavage results in decreased viral fitness compared to wild-type HIV.

  • 18. Su, Ting
    et al.
    Cheng, Jingdong
    Sohmen, Daniel
    Hedman, Rickard
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berninghausen, Otto
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wilson, Daniel N.
    Beckmann, Roland
    The force-sensing peptide VemP employs extreme compaction and secondary structure formation to induce ribosomal stalling2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e25642Article in journal (Refereed)
    Abstract [en]

    Interaction between the nascent polypeptide chain and the ribosomal exit tunnel can modulate the rate of translation and induce translational arrest to regulate expression of downstream genes. The ribosomal tunnel also provides a protected environment for initial protein folding events. Here, we present a 2.9 angstrom cryo-electron microscopy structure of a ribosome stalled during translation of the extremely compacted VemP nascent chain. The nascent chain forms two a-helices connected by an a-turn and a loop, enabling a total of 37 amino acids to be observed within the first 50-55 angstrom of the exit tunnel. The structure reveals how a-helix formation directly within the peptidyltransferase center of the ribosome interferes with aminoacyl-tRNA accommodation, suggesting that during canonical translation, a major role of the exit tunnel is to prevent excessive secondary structure formation that can interfere with the peptidyltransferase activity of the ribosome.

  • 19. Taylor, Gavin J.
    et al.
    Tichit, Pierre
    Schmidt, Marie D.
    Bodey, Andrew J.
    Rau, Christoph
    Baird, Emily
    Stockholm University, Faculty of Science, Department of Zoology. Lund University, Sweden.
    Bumblebee visual allometry results in locally improved resolution and globally improved sensitivity2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e0613Article in journal (Refereed)
    Abstract [en]

    The quality of visual information that is available to an animal is limited by the size of its eyes. Differences in eye size can be observed even between closely related individuals, yet we understand little about how this affects vision. Insects are good models for exploring the effects of size on visual systems because many insect species exhibit size polymorphism. Previous work has been limited by difficulties in determining the 3D structure of eyes. We have developed a novel method based on x-ray microtomography to measure the 3D structure of insect eyes and to calculate predictions of their visual capabilities. We used our method to investigate visual allometry in the bumblebee Bombus terrestris and found that size affects specific aspects of vision, including binocular overlap, optical sensitivity, and dorsofrontal visual resolution. This reveals that differential scaling between eye areas provides flexibility that improves the visual capabilities of larger bumblebees.

  • 20. Yeung, Kelvin
    et al.
    Boija, Ann
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Karlsson, Edvin
    Holmqvist, Per-Henrik
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tstskis, Yonit
    Nisoli, Ilaria
    Yap, Damian
    Lorzadeh, Alireza
    Moksa, Michelle
    Hirst, Martin
    Aparicio, Samuel
    Fanto, Manolis
    Stenberg, Per
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    McNeill, Helen
    Atrophin controls developmental signaling pathways via interactions with Trithorax-like2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, p. 1-24, article id e23084Article in journal (Refereed)
    Abstract [en]

    Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

  • 21. Zivanov, Jasenko
    et al.
    Nakane, Takanori
    Forsberg, Björn O.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kimanius, Dari
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hagen, Wim J. H.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Scheres, Sjors H. W.
    New tools for automated high-resolution cryo-EM structure determination in RELION-32018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e42166Article in journal (Refereed)
    Abstract [en]

    Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2-0.7 angstrom compared to previous RELION versions.

1 - 21 of 21
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