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  • 1.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lang, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lendel, Christofer
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Corrigendum to “Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly” [FEBS Lett. 586 (2012) 3991–3995]2013In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 9, p. 1452-1452Article in journal (Other academic)
  • 2.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lang, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lendel, Christofer
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Transient small molecule interactions kinetically modulate amyloid beta peptide self-assembly2012In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, no 22, p. 3991-3995Article in journal (Refereed)
    Abstract [en]

    Small organic molecules, like Congo red and lacmoid, have been shown to modulate the self-assembly of the amyloid beta peptide (A beta). Here, we show that A beta forms NMR invisible non-toxic co-aggregates together with lacmoid as well as Congo red. We find that the interaction involves two distinct kinetic processes and at every given time point only a small fraction of A beta is in the co-aggregate. These weak transient interactions kinetically redirect the aggregation prone A beta from self-assembling into amyloid fibrils. These findings suggest that even such weak binders might be effective as therapeutics against pathogenic protein aggregation.

  • 3.
    Arjona, Davinia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wikström, Mårten
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nitric oxide is a potent inhibitor of the cbb(3)-type heme-copper oxidases2015In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 589, no 11, p. 1214-1218Article in journal (Refereed)
    Abstract [en]

    C-type heme-copper oxidases terminate the respiratory chain in many pathogenic bacteria, and will encounter elevated concentrations of NO produced by the immune defense of the host. Thus, a decreased sensitivity to NO in C-type oxidases would increase the survival of these pathogens. Here we have compared the inhibitory effect of NO in C-type oxidases to that in the mitochondrial A-type. We show that O-2-reduction in both the Rhodobacter sphaeroides and Vibrio cholerae C-type oxidases is strongly and reversibly inhibited by submicromolar NO, with an inhibition pattern similar to the A-type. Thus, NO tolerance in pathogens with a C-type terminal oxidase has to rely mainly on other mechanisms.

  • 4.
    Bhushan, Shashi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kuhn, Claus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berglund, Anna-Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Roth, Christian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The role of the N-terminal domain of chloroplast targeting peptides in organellar protein import and miss-sorting2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 16, p. 3966-3972Article in journal (Refereed)
    Abstract [en]

    We have analysed 385 mitochondrial and 567 chloroplastic signal sequences of proteins found in the organellar proteomes of Arabidopsis thaliana. Despite overall similarities, the first 16 residues of transit peptides differ remarkably. To test the hypothesis that the N-terminally truncated transit peptides would redirect chloroplastic precursor proteins to mitochondria, we studied import of the N-terminal deletion mutants of ELIP, PetC and Lhcb2.1. The results show that the deletion mutants were neither imported into chloroplasts nor miss-targeted to mitochondria in vitro and in vivo, showing that the entire transit peptide is necessary for correct targeting as well as miss-sorting.

  • 5. Braun, Bernhard
    et al.
    Pfirrmann, Thorsten
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Menssen, Ruth
    Hofmann, Kay
    Scheel, Hartmut
    Wolf, Dieter H.
    Gid9, a second RING finger protein contributes to the ubiquitin ligase activity of the Gid complex required for catabolite degradation2011In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, no 24, p. 3856-3861Article in journal (Refereed)
    Abstract [en]

    The two major antagonistic pathways of carbon metabolism in cells, glycolysis and gluconeogenesis, are tightly regulated. In the eukaryotic model organism Saccharomyces cerevisiae the switch from gluconeogenesis to glycolysis is brought about by proteasomal degradation of the gluconeogenic enzyme fructose-1,6-bisphosphatase. The ubiquitin ligase responsible for polyubiquitylation of fructose-1,6-bisphosphatase is the Gid complex. This complex consists of seven subunits of which subunit Gid2/Rmd5 contains a RING finger domain providing E3 ligase activity. Here we identify an additional subunit containing a degenerated RING finger, Gid9/Fyv10. This subunit binds to Gid2/Rmd5. A mutation in the degenerated RING finger of Gid9/Fyv10 abolishes polyubiquitylation and degradation of three enzymes specific for gluconeogenesis. Structured summary of protein interactions: Gid2 physically interacts with Gid9 by anti tag coimmunoprecipitation (View interaction) (C) 2011 Federation of European Biochemical Societies.

  • 6. Bugaeva, Elizaveta Y.
    et al.
    Shpanchenko, Olga V.
    Felden, Brice
    Isaksson, Leif A.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Dontsova, Olga A.
    One SmpB molecule accompanies tmRNA during its passage through the ribosomes2008In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 582, no 10, p. 1532-1536Article in journal (Refereed)
    Abstract [en]

    tmRNA and SmpB are the main participants of trans-translation, a process which rescues the ribosome blocked during translation of non-stop mRNA. While a one-to-one stoichiometry of tmRNA to the ribosome is generally accepted, the number of SmpB molecules in the complex is still under question. We have isolated tmRNA-ribosome complexes blocked at different steps of the tmRNA path through the ribosome and analyzed the stoichiometry of the complexes. Ribosome, tmRNA and SmpB were found in equimolar amount in the tmRNA-ribosome complexes stopped at the position of the 2nd, 4th, 5th or the 11th codons of the coding part of the tmRNA. 

  • 7.
    Bárány-Wallje, Elsa
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gaur, Jugnu
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lundberg, Pontus
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Differential membrane perturbation caused by the cell penetrating peptide Tp10 depending on attached cargo2007In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 581, no 13, p. 2389-2393Article in journal (Refereed)
    Abstract [en]

    The membrane leakage caused by the cell penetrating peptide Tp10, a variant of transportan, was studied in large unilamellar vesicles with the entrapped fluorophore calcein. The vesicles were composed of zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. A significant decrease in membrane leakage was found when the 55 kDa streptavidin protein was attached to Tp10. When a 5.4 kDa peptide nucleic acid molecule was attached, the membrane leakage was comparable to that caused by Tp10 alone. The results suggest that direct membrane effects may cause membrane translocation of Tp10 alone and of smaller complexes, whereas these effects do not contribute for larger cargoes.

  • 8.
    Bäckman, Hans G
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pessoa, João
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Eneqvist, Therese
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Binding of divalent cations is essential for the activity of the organellar peptidasome in Arabidopsis thaliana, AtPreP.2009In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 583, no 17, p. 2727-33Article in journal (Refereed)
    Abstract [en]

    The dual-targeted mitochondrial and chloroplastic zinc metallooligopeptidase from Arabidopsis, AtPreP, functions as a peptidasome that degrades targeting peptides and other small unstructured peptides. In addition to Zn located in the catalytic site, AtPreP also contains two Mg-binding sites. We have investigated the role of Mg-binding using AtPreP variants, in which one or both sites were rendered unable to bind Mg(2+). Our results show that metal binding besides that of the active site is crucial for AtPreP proteolysis, particularly the inner site appears essential for normal proteolytic function. This is also supported by its evolutionary conservation among all plant species of PreP.

  • 9. Cuviello, Flavia
    et al.
    Tellgren-Roth, Åsa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lara, Patricia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ruud Selin, Frida
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Monné, Magnus
    Bisaccia, Faustino
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ostuni, Angela
    Membrane insertion and topology of the amino-terminal domain TMD0 of multidrug-resistance associated protein 6 (MRP6)2015In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 589, no 24, p. 3921-3928Article in journal (Refereed)
    Abstract [en]

    The function of the ATP-binding cassette transporter MRP6 is unknown but mutations in its gene cause pseudoxanthoma elasticum. We have investigated the membrane topology of the N-terminal transmembrane domain TMD0 of MRP6 and the membrane integration and orientation propensities of its transmembrane segments (TMs) by glycosylation mapping. Results demonstrate that TMD0 has five TMs, an Nout-Cin topology and that the less hydrophobic TMs have strong preference for their orientation in the membrane that affects the neighboring TMs. Two disease-causing mutations changing the number of positive charges in the loops of TMD0 did not affect the membrane insertion efficiencies of the adjacent TMs.

  • 10.
    Cymer, Florian
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ismail, Nurzian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Weak pulling forces exerted on N-in-orientated transmembrane segments during co-translational insertion into the inner membrane of Escherichia coli2014In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 588, no 10, p. 1930-1934Article in journal (Refereed)
    Abstract [en]

    Transmembrane helices (TMHs) in membrane proteins can be orientated with their N-terminus towards the cytoplasm (N-in), or facing the non-cytoplasmic side (N-out). Most membrane proteins are inserted co-translationally into membranes, aided by Sec-type translocons. Since the final orientation of N-in-and N-out-orientated TMHs differs, they could also interact differently with the translocon and the surrounding membrane during insertion. We measured pulling forces exerted on N-in-orientated TMHs during co-translational insertion into the inner membrane of Escherichia coli. Our results demonstrate that Nin-orientated TMHs experience a weaker pulling force but retain the overall biphasic force profile seen previously for Nout-orientated TMHs (Ismail et al., 2012 [1]).

  • 11. Eriksson, A M
    et al.
    Lundgren, B
    Andersson, K
    DePierre, J W
    Is the cytosolic catalase induced by peroxisome proliferators in mouse liver on its way to the peroxisomes?1992In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 308, no 2Article in journal (Refereed)
    Abstract [en]

    Dietary treatment of male C57B1/6 mice with clofibrate, nafenopin or WY-14.643 resulted in a modest (at most 2-fold) increase in the total catalase activity in the whole homogenate and mitochondrial fraction prepared from the livers of these animals. On the other hand, the catalase activity recovered in the cytosolic fraction was increased 12- to 18-fold, i.e. 30-35% of the total catalase activity in the hepatic homogenate was present in the high-speed supernatant fraction after treatment with these peroxisome proliferators. A study of the time course of the changes in peroxisomal and cytosolic catalase activities demonstrated that the peroxisomal activity both increased upon initiation of exposure and decreased after termination of treatment several days after the increase and decrease, respectively, in the corresponding cytosolic activity. This finding suggests that the cytosolic catalase may be on its way to incorporation into peroxisomes.

  • 12.
    Farías-Rico, José Arcadio
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Goetz, Sara Kathrin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Marino, Jacopo
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mutational analysis of protein folding inside the ribosome exit tunnel2017In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, no 1, p. 155-163Article in journal (Refereed)
    Abstract [en]

    Recent work has demonstrated that cotranslational folding of proteins or protein domains in, or in the immediate vicinity of, the ribosome exit tunnel generates a pulling force on the nascent polypeptide chain that can be detected using a so-called translational arrest peptide (AP) engineered into the nascent chain as a force sensor. Here, we show that AP-based force measurements combined with systematic Ala and Trp scans of a zinc-finger domain that folds in the exit tunnel can be used to identify the residues that are critical for intraribosomal folding. Our results suggest a general approach to characterize the folded state(s) that may form as a protein domain moves progressively down the ribosome exit tunnel.

  • 13.
    Gustafsson, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berntsson, Ronnie P-A
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Umeå University, Sweden.
    Martínez-Carranza, Markel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    El Tekle, Geniver
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Odegrip, Richard
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Johnson, Eric A.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster2017In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, no 22, p. 3781-3792Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins are highly toxic substances and are all encoded together with one of two alternative gene clusters, the HA or the OrfX gene cluster. Very little is known about the function and structure of the proteins encoded in the OrfX gene cluster, which in addition to the toxin contains five proteins (OrfX1, OrfX2, OrfX3, P47, and NTNH). We here present the structures of OrfX2 and P47, solved to 2.1 and 1.8 Å, respectively. We show that they belong to the TULIP protein superfamily, which are often involved in lipid binding. OrfX1 and OrfX2 were both found to bind phosphatidylinositol lipids.

  • 14.
    Gyllberg, Hanna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Löfgren, Kajsa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindegren, Heléne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bedecs, Katarina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Increased Src kinase level results in increased protein tyrosine phosphorylation in scrapie-infected neuronal cell lines.2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 11, p. 2603-8Article in journal (Refereed)
    Abstract [en]

    We have studied how prion infection may affect the Src kinase activity in three different neuronal cell lines, ScGT1 and ScN2a, where ScGT1 were generated in our laboratory. By immunoblotting, using clone 28 - a monoclonal antibody recognizing active Src, we have found a 32+/-6.3% and 75+/-7.7% elevation in Src activity in ScGT1 and ScN2a cells, respectively, compared to uninfected cells. Immunocomplex in vitro kinase assay confirmed the increased Src activity. The increased Src kinase activity in scrapie-infected cells was further shown to correlate to an increased level of Src protein. In addition, an important increase in the protein tyrosine phosphorylation signal was observed in ScGT1 and ScN2a cells, which was further shown to be Src-dependent, as treatment with PP2 - a Src family kinase specific inhibitor, reversed the protein tyrosine phosphorylation profile. Abnormal Src-kinase activation and subsequent protein tyrosine phosphorylation may be key elements in the neuropathology of the prion diseases.

  • 15.
    Herman, Maria Dolores
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nyman, Tomas
    Welin, Martin
    Lehtiö, Lari
    Flodin, Susanne
    Trésaugues, Lionel
    Kotenyova, Tetyana
    Flores, Alex
    Nordlund, Pär
    Completing the family portrait of the anti-apoptotic Bcl-2 proteins: Crystal structure of human Bfl-1 in complex with Bim2008In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 582, no 25-26, p. 3590-3594Article in journal (Refereed)
    Abstract [en]

    Evasion of apoptosis is recognized as a characteristic of malignant growth. Anti-apoptotic B-cell lymphoma-2 (Bcl-2) family members have therefore emerged as potential therapeutic targets due to their critical role in proliferating cancer cells. Here, we present the crystal structure of Bfl-1, the last anti-apoptotic Bcl-2 family member to be structurally characterized, in complex with a peptide corresponding to the BH3 region of the pro-apoptotic protein Bim. The structure reveals distinct features at the peptide-binding site, likely to define the binding specificity for pro-apoptotic proteins. Superposition of the Bfl-1:Bim complex with that of Mcl-1:Bim reveals a significant local plasticity of hydrophobic interactions contributed by the Bim peptide, likely to be the basis for the multi specificity of Bim for anti-apoptotic proteins.

  • 16.
    Holback, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Adlerz, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gatsinzi, Tom
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The APP processing enzyme ADAM10 is up-regulated by retinoic acid in a PI3-kinase-dependent mannerIn: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468Article in journal (Refereed)
  • 17.
    Holm, Tina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Netzereab, Semharai
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Hansen, Mats
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Hällbrink, Mattias
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Uptake of cell-penetrating peptides in yeasts2005In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 579, no 23, p. 5217-5222Article in journal (Refereed)
    Abstract [en]

    The uptake of different cell-penetrating peptides (CPPs) in two yeast species, Saccharomyces cerevisiae and Candida albicans, was studied using fluorescence HPLC-analyses of cell content. Comparison of the ability of penetratin, pVEC and (KFF)(3)K to traverse the yeast cell envelope shows that the cellular uptake of the peptides varies widely. Moreover, the intracellular degradation of the CPPs studied varies from complete stability to complete degradation. We show that intracellular degradation into membrane impermeable products can significantly contribute to the fluorescence signal. pVEC displayed highest internalizing capacity, and considering its stability in both yeast species, it is an attractive candidate for further studies.

  • 18.
    Kahle, Maximilian
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jareck, Sascha
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Insights into the mechanism of nitric oxide reductase from a Fe-B-depleted variant2019In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 593, no 12, p. 1351-1359Article in journal (Refereed)
    Abstract [en]

    A key step of denitrification, the reduction of toxic nitric oxide to nitrous oxide, is catalysed by cytochrome c-dependent NO reductase (cNOR). cNOR contains four redox-active cofactors: three hemes and a nonheme iron (Fe-B). Heme b(3) and Fe-B constitute the active site, but the specific mechanism of NO-binding events and reduction is under debate. Here, we used a recently constructed, fully folded and hemylated cNOR variant that lacks Fe-B to investigate the role of Fe-B during catalysis. We show that in the Fe-B-less cNOR, binding of both NO and O-2 to heme b(3) still occurs but further reduction is impaired, although to a lesser degree for O-2 than for NO. Implications for the catalytic mechanisms of cNOR are discussed.

  • 19.
    Košenina, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Masuyer, Geoffrey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Zhang, Sicai
    Dong, Min
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Crystal structure of the catalytic domain of the Weissella oryzae botulinum-like toxin2019In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 593, no 12, p. 1403-1410Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins (BoNTs) are the most potent toxins known. So far, eight serotypes have been identified that all act as zinc-dependent endopeptidases targeting SNARE proteins and inhibiting the release of neurotransmitters. Recently, the first botulinum toxin-like protein was identified outside the Clostridial genus, designated BoNT/Wo in the genome of Weissella oryzae. Here, we report the 1.6 angstrom X-ray crystal structure of the light chain of BoNT/Wo (LC/Wo). LC/Wo presents the core fold common to BoNTs but has an unusually wide, open and negatively charged catalytic pocket, with an additional Ca2+ ion besides the zinc ion and a unique ss-hairpin motif. The structural information will help establish the substrate profile of BoNT/Wo and help our understanding of how BoNT evolved.

  • 20.
    Lagerstedt, Jens
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Voss, JC
    Wieslander, Åke
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Persson, B L
    Structural modeling of dual-affinity purified Pho84 phosphate transporter2004In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 578, no 3, p. 262-268Article in journal (Refereed)
    Abstract [en]

    The phosphate transporter Pho84 of Saccharomyces cerevisiae is predicted to contain 12 transmembrane (TM) regions, divided into two partially duplicated parts of 6 TM segments. The three-dimensional (3D) organization of the Pho84 protein has not yet been determined. However, the 3D crystal structure of the Escherichia coli MFS glycerol-3-phosphate/phosphate antiporter, GlpT, and lactose transporter, LacY, has recently been determined. On the basis of extensive prediction and fold recognition analyses (at the MetaServer), GlpT was proposed as the best structural template on which the arrangement of TM segments of the Pho84 transporter was fit, using the comparative structural modeling program MODELLER. To initiate an evaluation of the appropriateness of the Pho84 model, we have performed two direct tests by targeting spin labels to putative TM segments 8 and 12. Electron paramagnetic resonance spectroscopy was then applied on purified and spin labeled Pho84. The line shape from labels located at both positions is consistent with the structural environment predicted by the template-generated model, thus supporting the model.

  • 21. Lee, Chiara
    et al.
    Kang, Hae Joo
    Hjelm, Anna
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Qureshi, Abdul Aziz
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nji, Emmanuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Choudhury, Hassanul
    Beis, Konstantinos
    de Gier, Jan-Willem
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Imperial College London, England.
    MemStar: A one-shot Escherichia coli-based approach for high-level bacterial membrane protein production2014In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 588, no 20, p. 3761-3769Article in journal (Refereed)
    Abstract [en]

    Optimising membrane protein production yields in Escherichia coli can be time- and resource-consuming. Here, we present a simple and effective Membrane protein Single shot amplification recipe: MemStar. This one-shot amplification recipe is based on the E. coli strain Lemo21(DE3), the PASM-5052 auto-induction medium and, contradictorily, an IPTG induction step. Using MemStar, production yields for most bacterial membrane proteins tested were improved to reach an average of 5 mg L-1 per OD600 unit, which is significantly higher than yields obtained with other common production strategies. With MemStar, we have been able to obtain new structural information for several transporters, including the sodium/proton antiporter NapA. (C) 2014 Federation of European Biochemical Societies.

  • 22.
    Lee, Hyun Ju
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The heme-copper oxidase superfamily shares a Zn2+-binding motif at the entrance to a proton pathway2013In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 6, p. 770-774Article in journal (Refereed)
    Abstract [en]

    Heme-copper oxidases (HCuOs) catalyse the reduction of oxygen, using the liberated free energy to maintain a proton-motive force across the membrane. In the mitochondrial-like A-type HCuOs, binding of heavy metal ions at the surface of the protein inhibits proton transfer. In bacterial C-type oxidases, the entry point to the proton pathway is on an accessory subunit unrelated to any subunit in A-type HCuOs. Despite this, we show here that heavy metal ions such as Zn2+ inhibit O-2-reduction very similarly in C-type as in A-type HCuOs, and furthermore that the binding site shares the same Glu-His motif. (C) 2013 Federation of European Biochemical Societies.

  • 23.
    Lundin, Camilla Rydström
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brzezinski, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Modulation of O-2 reduction in Saccharomyces cerevisiae mitochondria2017In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, no 24, p. 4049-4055Article in journal (Refereed)
    Abstract [en]

    Respiratory supercomplex factor (Rcf) 1 is a membrane-bound protein that modulates the activity of cytochrome c oxidase (CytcO) in Saccharomycescerevisiae mitochondria. To investigate this regulatory mechanism, we studied the interactions of CytcO with potassium cyanide (KCN) upon removal of Rcf Delta. While the addition of KCN to the wild-type mitochondria results in a full reduction of heme a, with the rcf Delta mitochondria, a significant fraction remains oxidized. Upon addition of ascorbate in the presence of O-2 and KCN, the reduction level of hemes a and b was a factor of similar to 2 larger with the wild-type than with the rcf Delta mitochondria. These data indicate that turnover of CytcO was less blocked in rcf Delta than in the wild-type mitochondria, suggesting that Rcf Delta modulates the structure of the catalytic site.

  • 24.
    Lundin, Carolina
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Johansson, Sofia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Johnson, Arthur E.
    Näslund, Jan
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Stable insertion of Alzheimer Aβ peptide into the ER membrane strongly correlates with its length2007In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 581, no 20, p. 3809-3813Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is characterized by the deposition of amyloid P-peptide (All) plaques in the brain. Full-length amyloid-beta precursor protein (APP) is processed by alpha- and beta-secretases to yield soluble APP derivatives and membrane-bound C-terminal fragments, which are further processed by gamma-secretase to a non-amyloidogenic 3 kDa product or to All fragments. As different A beta fragments contain different parts of the APP transmembrane helix, one may speculate that they are retained more or less efficiently in the membrane. Here, we use the translocon-mediated insertion of different APP-derived polypeptide segments into the endoplasmic reticulum membrane to assess the propensities for membrane retention of All fragments. Our results show a strong correlation between the length of an A beta-derived segment and its ability to integrate into the microsomal membrane.

  • 25.
    Lundin, Carolina
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Käll, Lukas
    Kreher, Scott A.
    Kapp, Katja
    Sonnhammer, Erik L.
    Carlson, John R.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane topology of the Drosophila OR83b odorant receptor2007In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 581, no 29, p. 5601-5604Article in journal (Refereed)
    Abstract [en]

    By analogy to mammals, odorant receptors (ORs) in insects, such as Drosophila melanogaster, have long been thought to belong to the G-protein coupled receptor (GPCR) superfamily. However, recent work has cast doubt on this assumption and has tentatively suggested an inverted topology compared to the canonical N-out - C-in 7 transmembrane (TM) GPCR topology, at least for some Drosophila ORs. Here, we report a detailed topology mapping of the Drosophila OR83b receptor using engineered glycosylation sites as topology markers. Our results are inconsistent with a classical GPCR topology and show that OR83b has an intracellular N-terminus, an extracellular C-terminus, and 7TM helices. (c) 2007 Federation of European Biochemical Societies.

  • 26.
    Lundin, Carolina
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nordström, Richard
    Wagner, Klaus
    Windpassinger, Christian
    Andersson, Helena
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Membrane topology of the human seipin protein2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 9, p. 2281-2284Article in journal (Refereed)
    Abstract [en]

    The Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) gene encodes an integral membrane protein, called seipin, of unknown function localized to the endoplasmic reticulum of eukaryotic cells. Seipin is associated with the heterogeneous genetic disease BSCL2, and mutations in an N-glycosylation motif links the protein to two other disorders, autosomal-dominant distal hereditary motor neuropathy type V and Silver syndrome. Here, we report a topological study of seipin using an in vitro topology mapping assay. Our results suggest that the predominant form of seipin is 462 residues long and has an N-cyt-C-cyt orientation with a long luminal loop between the two transmembrane helices.

  • 27. Marino, Jacopo
    et al.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Beckmann, Roland
    Small protein domains fold inside the ribosome exit tunnel2016In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 590, no 5, p. 655-660Article in journal (Refereed)
    Abstract [en]

    Cotranslational folding of small protein domains within the ribosome exit tunnel may be an important cellular strategy to avoid protein misfolding. However, the pathway of cotranslational folding has so far been described only for a few proteins, and therefore, it is unclear whether folding in the ribosome exit tunnel is a common feature for small protein domains. Here, we have analyzed nine small protein domains and determined at which point during translation their folding generates sufficient force on the nascent chain to release translational arrest by the SecM arrest peptide, both in vitro and in live E. coli cells. We find that all nine protein domains initiate folding while still located well within the ribosome exit tunnel.

  • 28.
    Nilsson, IngMarie
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Texas A&M University System Health Science Center, Texas.
    Johnson, Arthur E.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cleavage of a tail-anchored protein by signal peptidase2002In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 516, no 1-3, p. 106-108Article in journal (Refereed)
    Abstract [en]

    Tail-anchored proteins are post-translationally targeted and inserted into the endoplasmic reticulum membrane. They do not use the co-translational sign at-recognition particle (SRP)-dependent pathway, but rather utilize an ill-defined, ATP-dependent mechanism. Here, we show that a tail-anchored protein can be cleaved by signal peptidase and that the sequence requirements for efficient cleavage seem to be the same as for cleavage of co-translationally targeted SRP-dependent proteins.

  • 29.
    Norholm, Morten H. H.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Technical University of Denmark, Denmark.
    Toddo, Stephen
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Virkki, Minttu T. I.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Daley, Daniel O.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Improved production of membrane proteins in Escherichia coli by selective codon substitutions2013In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 15, p. 2352-2358Article in journal (Refereed)
    Abstract [en]

    Membrane proteins are extremely challenging to produce in sufficient quantities for biochemical and structural analysis and there is a growing demand for solutions to this problem. In this study we attempted to improve expression of two difficult-to-express coding sequences (araH and narK) for membrane transporters. For both coding sequences, synonymous codon substitutions in the region adjacent to the AUG start led to significant improvements in expression, whereas multi-parameter sequence optimization of codons throughout the coding sequence failed. We conclude that coding sequences can be re-wired for high-level protein expression by selective engineering of the 5' coding sequence with synonymous codons, thus circumventing the need to consider whole sequence optimization. (C) 2013 Federation of European Biochemical Societies.

  • 30.
    Näsvik Öjemyr, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Ballmoos, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gennis, Robert B.
    Department of Biochemistry, University of Illinois at Urbana-Champaign.
    Sligar, Stephen G.
    Department of Chemistry, University of Illinois at Urbana-Champaign.
    Brzezinski, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Reconstitution of respiratory oxidases in membrane nanodiscs for investigation of proton-coupled electron transfer2012In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, p. 640-645Article in journal (Refereed)
    Abstract [en]

    The function of membrane-bound transporters is commonly affected by the milieu of the hydrophobic, membrane-spanning part of the transmembrane protein. Consequently, functional studies of these proteins often involve incorporation into a native-like bilayer where the lipid components of the membrane can be controlled. The classical approach is to reconstitute the purified protein into liposomes. Even though the use of such liposomes is essential for studies of transmembrane transport processes in general, functional studies of the transporters themselves in liposomes suffer from several disadvantages. For example, transmembrane proteins can adopt two different orientations when reconstituted into liposomes, and one of these populations may be inaccessible to ligands, to changes in pH or ion concentration in the external solution. Furthermore, optical studies of proteins reconstituted in liposomes suffer from significant light scattering, which diminishes the signal-to-noise value of the measurements. One attractive approach to circumvent these problems is to use nanodiscs, which are phospholipid bilayers encircled by a stabilizing amphipathic helical membrane scaffold protein. These membrane nanodiscs are stable, soluble in aqueous solution without detergent and do not scatter light significantly. In the present study, we have developed a protocol for reconstitution of the aa3- and ba3-type cytochrome c oxidases into nanodiscs. Furthermore, we studied proton-coupled electron-transfer reactions in these enzymes with microsecond time resolution. The data show that the nanodisc membrane environment accelerates proton uptake in both oxidases.

  • 31. Ostuni, A.
    et al.
    Lara, Patricia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Armentano, M. F.
    Miglionico, R.
    Salvia, A. M.
    Monnich, M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Carmosino, M.
    Lasorsa, F. M.
    Monne, M.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bisaccia, F.
    The hepatitis B x antigen anti-apoptotic effector URG7 is localized to the endoplasmic reticulum membrane2013In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 18, p. 3058-3062Article in journal (Refereed)
    Abstract [en]

    Hepatitis B x antigen up-regulates the liver expression of URG7 that contributes to sustain chronic virus infection and to increase the risk for hepatocellular carcinoma by its anti-apoptotic activity. We have investigated the subcellular localization of URG7 expressed in HepG2 cells and determined its membrane topology by glycosylation mapping in vitro. The results demonstrate that URG7 is N-glycosylated and located to the endoplasmic reticulum membrane with an N-lumen-C-cytosol orientation. The results imply that the anti-apoptotic effect of URG7 could arise from the C-terminal cytosolic tail binding a pro-apoptotic signaling factor and retaining it to the endoplasmic reticulum membrane.

  • 32.
    Palombo, Isolde
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Daley, Daniel O.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Heme incorporation into the cytochrome bo(3) occurs at a late stage of assembly2012In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, no 23, p. 4197-4202Article in journal (Refereed)
    Abstract [en]

    Respiratory complexes in both prokaryotes and eukaryotes contain multiple co-factors, which are coordinated in defined positions so that they can function as electron wires. Intriguingly, co-factors are usually buried deep within hetero-oligomeric protein complexes and it is not clear when or how they are incorporated. In this study we show that heme is incorporated into the cytochrome bo(3) complex of Escherichia coli at a late stage of assembly. Specifically the apo-form of subunit I (the catalytic subunit) interacts with subunits III and IV before accepting heme. Assembly of subunit II is stalled until heme is incorporated.

  • 33.
    Petersson, Ulrika A.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kieselbach, Thomas
    García-Cerdán, José G.
    Schroöder, Wolfgang P.
    The Prx Q protein of Arabidopsis thaliana is a member of the luminal chloroplast proteome2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 26, p. 6055-6061Article in journal (Refereed)
    Abstract [en]

    Peroxiredoxins have been discovered in many organisms ranging from eubacteria to mammals, and their known biological functions include both oxidant defense and signal transduction. The genome of Arabidopsis thaliana encodes for ten individual peroxiredoxins, of which four are located in the chloroplast. The best-characterized member of the chloroplast peroxiredoxins is 2-Cys Prx that is associated with the stroma side of the thylakoid membrane and is considered to participate in antioxidant defense and protection of photosynthesis. This study addressed the chloroplast peroxiredoxin Prx Q and showed that its subcellular location is the lumen of the thylakoid membrane. To get insight in the biological function of the Prx Q protein of Arabidopsis, the protein levels of the Prx Q protein in thylakoid membranes were studied under different light conditions and oxidative stress. A T-DNA knockout mutant of Prx Q did not show any visible phenotype and had normal photosynthetic performance with a slightly increased oxygen evolving activity.

  • 34.
    Reithinger, Johannes H
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yim, Chewon
    Seoul National University.
    Park, Kwangjin
    Seoul National University.
    Björkholm, Patrik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kim, Hyun
    Seoul National University, Seoul, South Korea.
    A short C-terminal tail prevents mis-targeting of hydrophobic mitochondrial membrane proteins to the ER2013In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 21, p. 3480-6Article in journal (Refereed)
    Abstract [en]

    Sdh3/Shh3, a subunit of mitochondrial succinate dehydrogenase, contains transmembrane domains with a hydrophobicity comparable to that of endoplasmic reticulum (ER) proteins. Here, we show that a C-terminal reporter fusion to Sdh3/Shh3 results in partial mis-targeting of the protein to the ER. This mis-targeting is mediated by the signal recognition particle (SRP) and depends on the length of the C-terminal tail. These results imply that if nuclear-encoded mitochondrial proteins contain strongly hydrophobic transmembrane domains and a long C-terminal tail, they have the potential to be recognized by SRP and mis-targeted to the ER.

  • 35.
    Scaletti, Emma
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Jemth, Ann-Sofie
    Helleday, Thomas
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs2019In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 593, no 14, p. 1863-1873Article in journal (Refereed)
    Abstract [en]

    Serine hydroxymethyltransferase (SHMT) is the major source of 1-carbon units required for nucleotide synthesis. Humans have cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms, which are upregulated in numerous cancers, making the enzyme an attractive drug target. Here, we show that the antifolates lometrexol and pemetrexed are inhibitors of SHMT2 and solve the first SHMT2-antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT1 with antifolate bound hSHMT2 indicates a highly conserved active site architecture. This structural information offers insights as to how these compounds could be improved to produce more potent and specific inhibitors of this emerging anti-cancer drug target.

  • 36.
    Siegbahn, Per E. M.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mutations in the D-channel of cytochrome c oxidase causes leakage of the proton pump2014In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 588, no 4, p. 545-548Article in journal (Refereed)
    Abstract [en]

    It has experimentally been found that certain mutations close to the entry point of the proton transfer channel in cytochrome c oxidase stop proton translocation but not the oxygen reduction chemistry. This effect is termed uncoupling. Since the mutations are 20 angstrom away from the catalytic center, this is very surprising. A new explanation for this phenomenon is suggested here, involving a local effect at the entry point of the proton channel, rather than the long range effects suggested earlier. (C) 2013 Federation of European Biochemical Societies.

  • 37.
    Skaar, Karin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Claesson, Magnus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Odegrip, Richard
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Högbom, Magnus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Crystal structure of the bacteriophage P2 integrase catalytic domain2015In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 589, no 23, p. 3556-3563Article in journal (Refereed)
    Abstract [en]

    Bacteriophage P2 is a temperate phage capable of integrating its DNA into the host genome by site-specific recombination upon lysogenization. Integration and excision of the phage genome requires P2 integrase, which performs recognition, cleavage and joining of DNA during these processes. This work presents the high-resolution crystal structure of the catalytic domain of P2 integrase, and analysis of several non-functional P2 integrase mutants. The DNA binding area is characterized by a large positively charged patch, harbouring key residues. The structure reveals potential for large dimer flexibility, likely essential for rearrangement of DNA strands upon integration and excision.

  • 38.
    Svensson, Linda M.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jemth, Ann-Sofie
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Desroses, Matthieu
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Loseva, Olga
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Crystal structure of human MTH1 and the 8-oxo-dGMP product complex2011In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, no 16, p. 2617-2621Article in journal (Refereed)
    Abstract [en]

    MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9 angstrom) and its complex with the product 8-oxo-dGMP (1.8 angstrom). Unexpectedly MTH1 binds the nucleotide in the anti conformation with no direct interaction between the 8-oxo group and the protein. We suggest that the specificity depends on the stabilization of an enol tautomer of the 8-oxo form of dGTP. The binding of the product induces no major structural changes. The structures reveal the mode of nucleotide binding in MTH1 and provide the structural basis for inhibitor design.

  • 39.
    Österberg, Marie
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Botelho, Salomé Calado
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kim, Hyun
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Charged flanking residues control the efficiency of membrane insertion of the first transmembrane segment in yeast mitochondrial Mgm1p2011In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, no 8, p. 1238-1242Article in journal (Refereed)
    Abstract [en]

    Mgm1p is a nuclearly encoded GTPase important for mitochondrial fusion. Long and short isoforms of the protein are generated in a unique alternative topogenesis process in which the most N-terminal of two hydrophobic segments in the protein is inserted into the inner mitochondrial membrane in about half of the molecules and translocated across the inner membrane in the other half. In the latter population, the second hydrophobic segment is cleaved by the inner membrane protease Pcp1p, generating the short isoform. Here, we show that charged residues in the regions flanking the first segment critically affect the ratio between the two isoforms, providing new insight into the importance of charged residues in the insertion of proteins into the mitochondrial inner membrane.

1 - 39 of 39
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