Journal of Molecular Biology

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  • Developing Adnectins that Target SRC Co-Activator Binding to PXR; A Structural Approach Towards Understanding Promiscuity of PXR
    [Jan 2015]

    Publication date: Available online 8 January 2015
    Source:Journal of Molecular Biology

    Author(s): Javed A. Khan , Daniel M. Camac , Simon Low , Andrew Tebben , David L. Wensel , Martin C. Wright. , Julie Su , Victoria Jenny , Ruchira Das Gupta , Max Ruzanov , Katie A. Russo , Aneka Bell , Yongmi An , James W. Bryson , Mian Gao , Pallavi Gambhire , Eric Baldwin , Daniel Gardner , Cullen Cavallaro , John Duncia , John Hynes

    The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated “Adnectins,” derived from 10th fibronectin type III domain (10Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and a Chemokine Receptor-1 (CCR1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in targeting not only the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.
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  • Structural basis of dynamic membrane recognition by trans-Golgi network specific FAPP proteins
    [Jan 2015]

    Publication date: Available online 8 January 2015
    Source:Journal of Molecular Biology

    Author(s): Marc Lenoir , Michał Grzybek , Michał Majkowski , Sandya Rajesh , Jaswant Kaur , Sara B.-M. Whittaker , Ünal Coskun , Michael Overduin

    Glycosphingolipid metabolism relies on selective recruitment of the pleckstrin homology (PH) domains of FAPP proteins to the trans-Golgi network (TGN). The mechanism involved is unclear but requires recognition of phosphatidylinositol 4-phosphate (PI4P) within the Golgi membrane. We investigated the molecular basis of FAPP1-PH domain interactions with PI4P bilayers in liposome sedimentation and membrane partitioning assays. Our data reveals a mechanism in which FAPP-PH proteins preferentially target PI4P-containing liquid disordered membranes, while liquid ordered membranes were disfavored. Additionally, NMR spectroscopy was used to identify the binding determinants responsible for recognizing TGN-like bicelles including phosphoinositide and neighboring lipid molecules. Membrane penetration by the FAPP1-PH domain was mediated by an exposed, conserved hydrophobic wedge next to the PI4P recognition site and ringed by a network of complementary polar residues and basic charges. , Our data illuminates how insertion of a structured loop provides selectivity for sensing membrane fluidity and targeting to defined membrane zones and organelles. The determinants of this membrane sensing process are conserved across the CERT, OSBP and FAPP (COF) family. Hence lipid gradients result not only in differential membrane ordering along the secretory pathway, but also specifically localize diverse proteins through recognition of ensembles of lipid ligands in dynamic and deformable bilayers in order to promote anterograde trafficking.
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  • Structure and evolution of N-domains in AAA metalloproteases
    [Jan 2015]

    Publication date: Available online 8 January 2015
    Source:Journal of Molecular Biology

    Author(s): Franka Scharfenberg , Justyna Serek-Heuberger , Murray Coles , Marcus D. Hartmann , Michael Habeck , Jörg Martin , Andrei N. Lupas , Vikram Alva

    Metalloproteases of the AAA family play a crucial role in protein quality control within the cytoplasmic membrane of bacteria and the inner membrane of eukaryotic organelles. These membrane-anchored hexameric enzymes are composed of an N-terminal domain with one or two transmembrane helices, a central AAA ATPase module and a C-terminal Zn2+-dependent protease. While the latter two domains have been well studied, so far little is known about the N-terminal regions. Here, in an extensive bioinformatic and structural analysis, we identified three major, non-homologous groups of N-domains in AAA metalloproteases. By far the largest one is the FtsH-like group of bacteria and eukaryotic organelles. The other two groups are specific to Yme1, one found in plants, fungi, and basal metazoans, and the other exclusively in animals. Using NMR and crystallography, we determined the subunit structure and hexameric assembly of E. coli FtsH-N, exhibiting an unusual α+β fold, and the conserved part of fungal Yme1-N from Saccharomyces cerevisiae, revealing a tetratricopeptide repeat (TPR) fold. Our bioinformatic analysis showed that, uniquely among these proteins, the N-domain of Yme1 from the cnidarian Hydra vulgaris contains both the TPR region seen in basal metazoans and a region of homology to the N-domains of animals. It thus is a modern-day representative of an intermediate in the evolution of animal Yme1 from basal eukaryotic precursors.
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  • The sum is more than the parts: Crystal and solution data reveal that the PIDDosome core complex is a dynamic assembly
    [Jan 2015]

    Publication date: Available online 6 January 2015
    Source:Journal of Molecular Biology

    Author(s): Remco Sprangers







    Categories: Journal Articles
  • Bactobolin A binds to a site on the 70S ribosome distinct from previously seen antibiotics
    [Jan 2015]

    Publication date: Available online 3 January 2015
    Source:Journal of Molecular Biology

    Author(s): Alexey Amunts , Karol Fiedorczuk , Thao T. Truong , Josephine Chandler , E. Peter Greenberg , V. Ramakrishnan

    The ribosome is the target of a large number of antibiotics. Here, we report a 3.4Å resolution crystal structure of bactobolin A bound to 70S ribosome-tRNA complex. The antibiotic binds at a previously unseen site in the 50S subunit, and displaces tRNA bound at the P-site. It thus likely has a similar mechanism of action as Blasticidin S despite binding to a different site. The structure also rationalizes previously identified resistance mutations.
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  • Intrinsically Disordered C-terminal Tails of E. coli Single Stranded DNA Binding Protein Regulate Cooperative Binding to Single Stranded DNA
    [Jan 2015]

    Publication date: Available online 3 January 2015
    Source:Journal of Molecular Biology

    Author(s): Alexander G. Kozlov , Elizabeth Weiland , Anuradha Mittal , Vince Waldman , Edwin Antony , Nicole Fazio , Rohit V. Pappu , Timothy M. Lohman

    The homotetrameric E. coli single stranded DNA binding (SSB) protein plays a central role in DNA replication, repair and recombination. E. coli SSB can bind to long single-stranded (ss) DNA in multiple binding modes using all four subunits ((SSB)65 mode) or only two subunits ((SSB)35 binding mode), with the binding mode preference regulated by salt concentration and SSB binding density. These binding modes display very different ssDNA binding properties with the (SSB)35 mode displaying highly cooperative binding to ssDNA. SSB tetramers also bind an array of partner proteins, recruiting them to their sites of action. This is achieved through interactions with the last 9 amino acids (acidic tip) of the intrinsically disordered linkers (IDLs) within the four C-terminal tails connected to the ssDNA binding domains. Here we show that the amino acid composition and length of the IDL affects the ssDNA binding mode preferences of SSB protein. Surprisingly the number of IDLs and the lengths of individual IDLs together with the acidic tip contribute to highly cooperative binding in the (SSB)35 binding mode. Hydrodynamic studies and atomistic simulations suggest that the E. coli SSB IDLs show a preference for forming an ensemble of globular conformations, whereas the IDL from Plasmodium falciparum SSB forms an ensemble of more extended random coils. The more globular conformations correlate with cooperative binding.
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  • Oligosaccharide and substrate binding in the starch debranching enzyme barley limit dextrinase
    [Jan 2015]

    Publication date: Available online 3 January 2015
    Source:Journal of Molecular Biology

    Author(s): Marie S. Møller , Michael S. Windahl , Lyann Sim , Marie Bøjstrup , Maher Abou Hachem , Ole Hindsgaul , Monica Palcic , Birte Svensson , Anette Henriksen

    Complete hydrolytic degradation of starch requires hydrolysis of both the α-1,4- and α-1,6-glucosidic bonds in amylopectin. Limit dextrinase is the only endogenous barley enzyme capable of hydrolyzing the α-1,6-glucosidic bond during seed germination and impaired limit dextrinase activity inevitably reduces the maltose and glucose yields from starch degradation. Crystal structures of barley limit dextrinase and active site mutants with natural substrates, products and substrate analogues were sought to better understand the facets of limit dextrinase–substrate interactions that confine high activity of limit dextrinase to branched malto-oligosaccharides. For the first time, an intact α-1,6-glucosidically linked substrate spanning the active site of a limit dextrinase or pullulanase has been trapped and characterized by crystallography. The crystal structure reveals both the branch and main chain binding sites and is used to suggest a mechanism for nucleophilicity enhancement in the active site. The substrate, product and analogue complexes were further used to outline substrate binding subsites, substrate binding restraints and to suggest a mechanism for avoidance of dual α-1,6- and α-1,4-hydrolytic activity likely to be a biological necessity during starch synthesis.
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  • By Any Means Necessary: Discovering a BCL-xL Specific Domain
    [Jan 2015]

    Publication date: Available online 31 December 2014
    Source:Journal of Molecular Biology

    Author(s): Kurt D. Deshayes







    Categories: Journal Articles
  • Titin and Obscurin: Giants Holding Hands and Discovery of a New Ig Domain Subset
    [Jan 2015]

    Publication date: Available online 31 December 2014
    Source:Journal of Molecular Biology

    Author(s): Guy M. Benian , Olga Mayans







    Categories: Journal Articles
  • Why Is Nuclear Organization Dynamic, Hierarchical and Intricate? Implications for Gene Regulation, Cellular Differentiation and Disease
    [Jan 2015]

    Publication date: Available online 30 December 2014
    Source:Journal of Molecular Biology

    Author(s): Marina Ostankovitch , Evi Soutoglou







    Categories: Journal Articles
  • Structure and interactions of the CS domain of human H/ACA RNP assembly protein Shq1
    [Jan 2015]

    Publication date: Available online 29 December 2014
    Source:Journal of Molecular Biology

    Author(s): Mahavir Singh , Zhonghua Wang , Duilio Cascio , Juli Feigon

    Shq1 is an essential protein involved in the early steps of biogenesis and assembly of H/ACA RNPs. Shq1 binds to dyskerin (Cbf5 in yeast) at an early step of H/ACA RNP assembly and is subsequently displaced by the H/ACA RNA. Shq1 contains an N-terminal CS and a C-terminal Shq1-specific domain (SSD). Dyskerin harbors many dyskeratosis congenita (DC) associated mutations. Structures of yeast Shq1 SSD bound to Cbf5 revealed that only a subset of these mutations is in the SSD binding site, implicating another subset in the putative CS binding site. Here we present the crystal structure of human Shq1 CS (hCS) and the NMR and crystal structure of hCS containing a serine substitution for proline 22 that is associated with some prostate cancers. The structure of hCS is similar to yeast Shq1 CS domain (yCS) and consists of two β-sheets that form an immunoglobulin-like β-sandwich fold. The N-terminal affinity tag sequence AHHHHHH associates with a neighboring protein in the crystal lattice to form an extra β-strand. Deletion of this tag was required to get spectra suitable for NMR structure determination, while the tag was required for crystallization. NMR chemical shift perturbation (CSP) experiments with dyskerin and Cbf5 derived peptides from putative CS binding sites revealed a conserved surface on CS important for Cbf5/dyskerin binding. A HADDOCK docking model of a Shq1-Cbf5 complex that defines the position of CS domain in the pre-H/ACA RNP was calculated using the CSP data.
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  • Conformational Preferences Underlying Reduced Activity of a Thermophilic Ribonuclease H
    [Jan 2015]

    Publication date: Available online 27 December 2014
    Source:Journal of Molecular Biology

    Author(s): Kate A. Stafford , Nikola Trbovic , Joel A. Butterwick , Robert Abel , Richard A. Friesner , Palmer Arthur G. III

    The conformational basis for reduced activity of the thermophilic ribonuclease HI enzyme from Thermus thermophilus, compared to its mesophilic homolog from Escherichia coli, is elucidated using a combination of NMR spectroscopy and molecular dynamics (MD) simulations. Explicit-solvent all-atom MD simulations of the two wild-type proteins as well as an E. coli mutant in which a glycine residue is inserted after position 80 to mimic the T. thermophilus protein reproduce the differences in conformational dynamics determined from 15 N spin relaxation NMR spectroscopy of three loop regions that surround the active site and contain functionally important residues: the glycine-rich region, the handle region, and the β5/αE loop. Examination of the MD trajectories indicates that the thermophilic protein samples conformations productive for substrate binding and activity less frequently than the mesophilic enzyme, although these differences may manifest as either increased or decreased relative flexibility of the different regions. Additional MD simulations indicate that mutations increasing activity of the T. thermophilus enzyme at mesophilic temperatures do so by reconfiguring the local environments of the mutated sites to more closely resemble active conformations. Taken together, the results show that both locally increased and decreased flexibility contribute to an overall reduction in activity of T. thermophilus ribonuclease H compared to its mesophilic E. coli homolog.
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    Categories: Journal Articles
  • Novel essential gene involved in 16S rRNA processing in Escherichia coli
    [Jan 2015]

    Publication date: Available online 26 December 2014
    Source:Journal of Molecular Biology

    Author(s): Tatsuaki Kurata , Shinobu Nakanishi , Masayuki Hashimoto , Masato Taoka , Yukiko Yamazaki , Toshiaki Isobe , Jun-ichi Kato

    Biogenesis of ribosomes is a complex process mediated by many factors. While its transcription proceeds, ribosomal RNA (rRNA) folds itself into a characteristic three dimensional structure through interaction with ribosomal proteins, during which its ends are processed. Here, we show that the essential protein YqgF, a RuvC family protein with an RNase H-like motif, is involved in the processing of pre-16S rRNA during ribosome maturation. Indeed, pre-16S rRNA accumulated in cells of a temperature-sensitive yqgF mutant (yqgFts ) cultured at a non-permissive temperature. In addition, purified YqgF was shown to process the 5’-end of pre-16S rRNA within 70S ribosomes in vitro. Mass spectrometry analysis of the total proteins in the yqgFts mutant cells showed that the expression of genes containing multiple Shine-Dalgarno-like sequences was observed to be lower than in wild-type. These results are interpreted to indicate that YqgF is involved in a novel enzymic activity necessary for the processing of pre-16S rRNA, thereby affecting elongation of translation.
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  • The Cobalamin-Independent Methionine Synthase Enzyme Captured in a Substrate-Induced Closed Conformation
    [Jan 2015]

    Publication date: Available online 26 December 2014
    Source:Journal of Molecular Biology

    Author(s): Devinder K. Ubhi , Jon D. Robertus

    The cobalamin-independent methionine synthase enzyme catalyzes a challenging reaction: the direct transfer of a methyl from 5-methyl-tetrahydrofolate-glutamate3 to the l-homocysteine thiol. The enzyme has a dual (βα)8 TIM barrel structure that binds, activates and brings the reactants into reaction proximity by conformational movements. In the previously observed open structures, the substrates bind too far apart to react, but we have captured a ternary complex with both substrates bound in a closed form of the enzyme. The closing is described in terms of a hinge between the N- and C-terminal TIM barrels and a rearrangement of key loops within the C domain. The substrate specificity can now be rationalized and the structure reveals His707 as the acid that protonates the THF leaving group through a water molecule trapped in the closed active site. The substrates are correctly oriented for an in-line attack by l-homocysteine on the N 5-methyl.
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  • Structure of Salmonella FlhE, conserved member of a flagellar Type III secretion operon
    [Jan 2015]

    Publication date: Available online 26 December 2014
    Source:Journal of Molecular Biology

    Author(s): Jaemin Lee , Arthur F. Monzingo , Adrian T. Keatinge-Clay , Rasika M. Harshey

    The bacterial flagellum is assembled by a multicomponent transport apparatus categorized as a Type III secretion (T3S) system. The secretion of proteins that assemble into the flagellum is driven by the proton motive force. The periplasmic protein FlhE is a member of the flhBAE operon in the majority of bacteria where FlhE is found. FlhA and FlhB are established components of the flagellar T3S system. The absence of FlhE results in a proton leak through the flagellar system, inappropriate secretion patterns, and cell death, indicating that FlhE regulates an important aspect of proper flagellar biosynthesis. We isolated FlhE from the periplasm of Salmonella and solved its structure to 1.5Å resolution. Possible roles of FlhE, including that of a chaperone, are discussed.
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  • Differential Role of Base Pairs on gal Promoters Strength
    [Jan 2015]

    Publication date: Available online 24 December 2014
    Source:Journal of Molecular Biology

    Author(s): Dale E.A. Lewis , Phuoc Le , Sankar Adhya

    Sequence alignments of promoters in prokaryotes postulated that the frequency of occurrence of a base pair at a given position of promoter elements reflects its contribution to intrinsic promoter strength. We directly assessed the contribution of the four base pairs in each position in the intrinsic promoter strength by keeping the context constant in Escherichia coli cAMP-CRP (cAMP receptor protein) regulated gal promoters by in vitro transcription assays. First, we show that base pair frequency within known consensus elements correlates well with promoter strength. Second, we observe some substitutions upstream of the ex-10 TG motif that are important for promoter function. Although the galP1 and P2 promoters overlap, only three positions where substitutions inactivated both promoters were found. We propose that RNA polymerase binds to the −12T base pair as part of double-stranded DNA while opening base pairs from −11A to +3 to form the single-stranded transcription bubble DNA during isomerization. The cAMP-CRP complex rescued some deleterious substitutions in the promoter region. The base pair roles and their flexibilities reported here for E. coli gal promoters may help construction of synthetic promoters in gene circuitry experiments in which overlapping promoters with differential controls may be warranted.
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  • Phosphomimetic mutation of the N-terminal lid of MDM2 enhances the polyubiquitination of p53 through stimulation of E2-ubiquitin thioester hydrolysis
    [Jan 2015]

    Publication date: Available online 24 December 2014
    Source:Journal of Molecular Biology

    Author(s): Jennifer A. Fraser , Erin G. Worrall , Yao Lin , Vivien Landre , Susanne Pettersson , Elizabeth Blackburn , Malcolm Walkinshaw , Petr Muller , Borek Vojtesek , Kathryn Ball , Ted R. Hupp

    MDM2 has a phosphorylation site within a lid motif at Ser17 whose phospho-mimetic mutation to Asp17 stimulates MDM2-mediated polyubiquitination of p53. MDM2 lid deletion, but not Asp17 mutation, induced a blue-shift in the λmax of intrinsic fluorescence derived from residues in the central domain including Trp235, Trp303, Trp323, and Trp329. This indicates that the Asp17 mutation does not alter the conformation of MDM2 surrounding the tryptophan residues. In addition, Phe235 mutation enhanced MDM2 binding to p53 but did not stimulate its’ ubiquitination function, thus uncoupling increases in p53 binding from its’ E3 ubiquitin ligase function. However, the Asp17 mutation in MDM2 stimulated its discharge of the UBCH5a-Ubiquitin thioester adduct. This stimulation of ubiquitin discharge from E2 was independent of the p53 substrate. There are now four known effects of the Asp17 mutation on MDM2; (i) it alters the conformation of the isolated N-terminus as defined by NMR; (ii) it induces increased thermostability of the isolated N-terminal domain; (iii) it stimulates the allosteric interaction of MDM2 with the DNA-binding domain of p53; and (iv) it stimulates a novel protein-protein interaction with the E2- ubiquitin complex in the absence of substrate p53 that in turns increases hydrolysis of the E2- ubiquitin thioester bond. These data also suggest a new strategy to disrupt MDM2 function by targetting the E2- ubiquitin discharge reaction.
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  • Assembly States of FliM and FliG within the Flagellar Switch Complex
    [Jan 2015]

    Publication date: Available online 20 December 2014
    Source:Journal of Molecular Biology

    Author(s): Ria Sircar , Peter P. Borbat , Michael J. Lynch , Jaya Bhatnagar , Matthew S. Beyersdorf , Christopher J. Halkides , Jack H. Freed , Brian R. Crane

    At the base of the bacterial flagella, a cytoplasmic rotor (the C-ring) generates torque and reverses rotation sense in response to stimuli. The bulk of the C-ring forms from many copies of the proteins FliG, FliM, and FliN, which together constitute the switch complex. To help resolve outstanding issues regarding C-ring architecture, we have investigated interactions between FliM and FliG from Thermotoga maritima with X-ray crystallography and pulsed dipolar ESR spectroscopy (PDS). A new crystal structure of an 11-unit FliG:FliM complex produces a large arc with a curvature consistent with the dimensions of the C-ring. Previously determined structures along with this new structure provided a basis to test switch complex assembly models. PDS combined with mutational studies and targeted cross-linking reveal that FliM and FliG interact through their middle domains to form both parallel and antiparallel arrangements in solution. Residue substitutions at predicted interfaces disrupt higher-order complexes that are primarily mediated by contacts between the C-terminal domain of FliG and the middle domain of a neighboring FliG molecule. Spin separations among multi-labeled components fit a self-consistent model that agree well with electron microscopy images of the C-ring. An activated form of the response regulator CheY destabilizes the parallel arrangement of FliM molecules to perturb FliG alignment in a process that may reflect the onset of rotation switching. These data suggest a model of C-ring assembly in which intermolecular contacts among FliG domains provide a template for FliM assembly and cooperative transitions.
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    Categories: Journal Articles
  • The Basis of Asymmetry in the SecA:SecB Complex
    [Jan 2015]

    Publication date: Available online 19 December 2014
    Source:Journal of Molecular Biology

    Author(s): Yuying Suo , Simon J.S. Hardy , Linda L. Randall

    During export in Escherichia coli, SecB, a homotetramer structurally organized as a dimer of dimers, forms a complex with two protomers of SecA, which is the ATPase that provides energy to transfer a precursor polypeptide through the membrane via the SecYEG translocon. There are two areas of contact on SecB that stabilize the SecA:SecB complex: the flat sides of the SecB tetramer and the C-terminal 13 residues of SecB. These contacts within the complex are distributed asymmetrically. Breaking contact between SecA and the sides of SecB results in release of only one protomer of SecA yielding a complex of stoichiometry SecA1:SecB4. This complex mediates export; however, the coupling of ATP hydrolysis to movements of the precursor through the translocon is much less efficient than the coupling by the SecA2:SecB4 complex. Here we used heterotetrameric species of SecB to understand the source of the asymmetry in the contacts and its role in the functioning of the complex. The model of interactions presented suggests a way that binding between SecA and SecB might decrease the affinity of precursor polypeptides for SecB and facilitate the transfer to SecA.
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    Categories: Journal Articles
  • Simultaneous Sequence-Based Prediction of the Statistical Populations of Ordered and Disordered Regions in Proteins
    [Jan 2015]

    Publication date: Available online 19 December 2014
    Source:Journal of Molecular Biology

    Author(s): Pietro Sormanni , Carlo Camilloni , Piero Fariselli , Michele Vendruscolo

    Extensive amounts of information about protein sequences are becoming available, as demonstrated by the over 79 million entries in the UniProt database. Yet, it is still challenging to obtain proteome-wide experimental information on the structural properties associated with these sequences. To bridge this gap, fast computational predictors of secondary structure and of intrinsic disorder of proteins have been developed. These two types of predictions, however, have remained largely separated, often preventing a clear characterisation of the structure and dynamics of proteins. Here, we introduce a computational method to predict secondary structure populations from amino acid sequences, which characterises simultaneously structure and disorder in a unified statistical mechanics framework. To develop this method, called s2D, we exploited recent advances made in the analysis of NMR chemical shifts that provide quantitative information about the probability distributions of secondary structure elements in disordered states. The results that we discuss show that the s2D method predicts secondary structure populations with an average error of about 14%. A validation on three datasets of, respectively, mostly disordered, mostly structured, and partly structured proteins show that its performance is comparable or better than that of existing predictors of intrinsic disorder and of secondary structure. These results indicate that it is possible to perform rapid and quantitative sequence-based characterisations of the structure and dynamics of proteins through the predictions of the statistical distributions of their ordered and disordered regions.
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    Categories: Journal Articles