Molecular evolution of protein conformational changes revealed by a network of evolutionarily coupled residues.

An improved understanding of protein conformational changes has broad implications for elucidating the mechanisms of various biological processes and for the design of protein engineering experiments. Understanding rearrangements of residue interactions is a key component in the challenge of describing structural transitions. Evolutionary properties of protein sequences and structures are extensively studied; however, evolution of protein motions, especially with respect to interaction rearrangements, has yet to be explored. Here, we investigated the relationship between sequence evolution and protein conformational changes and discovered that structural transitions are encoded in amino acid sequences as coevolving residue pairs. Furthermore, we found that highly coevolving residues are clustered in the flexible regions of proteins and facilitate structural transitions by forming and disrupting their interactions cooperatively. Our results provide insight into the evolution of protein conformational changes and help to identify residues important for structural transitions.

[1]  C. Yanofsky,et al.  Protein Structure Relationships Revealed by Mutational Analysis , 1964, Science.

[2]  A. Mclachlan.  Tests for comparing related amino-acid sequences. Cytochrome c and cytochrome c 551 . , 1971, Journal of molecular biology.

[3]  G A Petsko,et al.  Fluctuations in protein structure from X-ray diffraction. , 1984, Annual review of biophysics and bioengineering.

[4]  W. Kabsch,et al.  Refined crystal structure of the triphosphate conformation of H‐ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis. , 1990, The EMBO journal.

[5]  S H Kim,et al.  Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. , 1992, Science.

[6]  A. Wittinghofer,et al.  Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity , 1992, Molecular and cellular biology.

[7]  C. Sander,et al.  Correlated mutations and residue contacts in proteins , 1994, Proteins.

[8]  C. Sander,et al.  Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations? , 1994, Protein engineering.

[9]  M. Vihinen,et al.  Accuracy of protein flexibility predictions , 1994, Proteins.

[10]  E. Neher.  How frequent are correlated changes in families of protein sequences? , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Y. Zhao,et al.  Crystal structure implies that cyclophilin predominantly catalyzes the trans to cis isomerization. , 1996, Biochemistry.

[12]  T L Blundell,et al.  Symmetry, stability, and dynamics of multidomain and multicomponent protein systems. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  E D Laue,et al.  Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein. , 1997, Biochemistry.

[14]  D. Kahn,et al.  Structural transitions in the FixJ receiver domain. , 1999, Structure.

[15]  B. Rost,et al.  Effective use of sequence correlation and conservation in fold recognition. , 1999, Journal of molecular biology.

[16]  D. Kahn,et al.  Conformational changes induced by phosphorylation of the FixJ receiver domain. , 1999, Structure.

[17]  R. Nussinov,et al.  Folding and binding cascades: shifts in energy landscapes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Ranganathan,et al.  Evolutionarily conserved pathways of energetic connectivity in protein families. , 1999, Science.

[19]  Honggao Yan,et al.  Catalytic center assembly of HPPK as revealed by the crystal structure of a ternary complex at 1.25 A resolution. , 2000, Structure.

[20]  R. Russell,et al.  Analysis and prediction of functional sub-types from protein sequence alignments. , 2000, Journal of molecular biology.

[21]  R. Jernigan,et al.  Anisotropy of fluctuation dynamics of proteins with an elastic network model. , 2001, Biophysical journal.

[22]  Frederick W. Dahlquist,et al.  Studying excited states of proteins by NMR spectroscopy , 2001, Nature Structural Biology.

[23]  J Skolnick,et al.  Universal similarity measure for comparing protein structures. , 2001, Biopolymers.

[24]  J. Błaszczyk,et al.  Structure and dynamics of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase. , 2001, Journal of molecular graphics & modelling.

[25]  D. A. Bosco,et al.  Enzyme Dynamics During Catalysis , 2002, Science.

[26]  P. Agarwal,et al.  Network of coupled promoting motions in enzyme catalysis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Itay Mayrose,et al.  Rate4Site: an algorithmic tool for the identification of functional regions in proteins by surface mapping of evolutionary determinants within their homologues , 2002, ISMB.

[28]  Christopher J. Oldfield,et al.  Evolutionary Rate Heterogeneity in Proteins with Long Disordered Regions , 2002, Journal of Molecular Evolution.

[29]  Julie D Thompson,et al.  Multiple Sequence Alignment Using ClustalW and ClustalX , 2003, Current protocols in bioinformatics.

[30]  M E J Newman.  Assortative mixing in networks. , 2002, Physical review letters.

[31]  A. Horovitz,et al.  Mapping pathways of allosteric communication in GroEL by analysis of correlated mutations , 2002, Proteins.

[32]  Mark Gerstein,et al.  MolMovDB: analysis and visualization of conformational change and structural flexibility , 2003, Nucleic Acids Res..

[33]  Gürol M. Süel,et al.  Evolutionarily conserved networks of residues mediate allosteric communication in proteins , 2003, Nature Structural Biology.

[34]  S. Vucetic,et al.  Flavors of protein disorder , 2003, Proteins.

[35]  Michael Feig,et al.  MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology. , 2004, Journal of molecular graphics & modelling.

[36]  Richard W. Aldrich,et al.  A perturbation-based method for calculating explicit likelihood of evolutionary co-variance in multiple sequence alignments , 2004, Bioinform..

[37]  Mark Gerstein,et al.  Exploring the range of protein flexibility, from a structural proteomics perspective. , 2004, Current opinion in chemical biology.

[38]  Gil Amitai,et al.  Network analysis of protein structures identifies functional residues. , 2004, Journal of molecular biology.

[39]  R. Aldrich,et al.  Influence of conservation on calculations of amino acid covariance in multiple sequence alignments , 2004, Proteins.

[40]  Robert C. Edgar,et al.  MUSCLE: multiple sequence alignment with high accuracy and high throughput. , 2004, Nucleic acids research.

[41]  G. Gloor,et al.  Mutual information in protein multiple sequence alignments reveals two classes of coevolving positions. , 2005, Biochemistry.

[42]  Marvin Edelman,et al.  The limit of accuracy of protein modeling: influence of crystal packing on protein structure. , 2005, Journal of molecular biology.

[43]  Michael S. Rosenberg,et al.  Multiple sequence alignment accuracy and evolutionary distance estimation , 2005, BMC Bioinformatics.

[44]  I. Bahar,et al.  Structural changes involved in protein binding correlate with intrinsic motions of proteins in the unbound state. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  E. Eisenmesser,et al.  Enzyme dynamics during catalysis measured by NMR spectroscopy. , 2005, Methods in enzymology.

[46]  Frank Noé,et al.  Automated computation of low‐energy pathways for complex rearrangements in proteins: Application to the conformational switch of Ras p21 , 2005, Proteins.

[47]  Jianpeng Ma,et al.  The role of shape in determining molecular motions. , 2005, Biophysical journal.

[48]  L. Kay,et al.  Intrinsic dynamics of an enzyme underlies catalysis , 2005, Nature.

[49]  R. Ebright,et al.  Dynamically driven protein allostery , 2006, Nature Structural &Molecular Biology.

[50]  R. Nussinov,et al.  Residue centrality, functionally important residues, and active site shape: Analysis of enzyme and non‐enzyme families , 2006, Protein science : a publication of the Protein Society.

[51]  Lewis E. Kay,et al.  New Tools Provide New Insights in NMR Studies of Protein Dynamics , 2006, Science.

[52]  Peter B. McGarvey,et al.  UniRef: comprehensive and non-redundant UniProt reference clusters , 2007, Bioinform..

[53]  Carla Mattos,et al.  Transformation efficiency of RasQ61 mutants linked to structural features of the switch regions in the presence of Raf. , 2007, Structure.

[54]  Michael D. Daily,et al.  Local motions in a benchmark of allosteric proteins , 2007, Proteins.

[55]  Ruth Nussinov,et al.  Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR , 2007, PLoS Comput. Biol..

[56]  M. Sansom,et al.  Conformational change in an MFS protein: MD simulations of LacY. , 2007, Structure.

[57]  Csaba Böde,et al.  Network analysis of protein dynamics , 2007, FEBS letters.

[58]  Mark A. Wilson,et al.  Intrinsic motions along an enzymatic reaction trajectory , 2007, Nature.

[59]  Dmitrij Frishman,et al.  Co-evolving residues in membrane proteins , 2007, Bioinform..

[60]  Jeffrey J. Gray,et al.  Contact rearrangements form coupled networks from local motions in allosteric proteins , 2008, Proteins.

[61]  Tim J. P. Hubbard,et al.  Data growth and its impact on the SCOP database: new developments , 2007, Nucleic Acids Res..

[62]  Harel Weinstein,et al.  An Intracellular Interaction Network Regulates Conformational Transitions in the Dopamine Transporter* , 2008, Journal of Biological Chemistry.

[63]  Alfonso Valencia,et al.  Protein co-evolution, co-adaptation and interactions , 2008, The EMBO journal.

[64]  Lukasz A. Kurgan,et al.  Accurate sequence-based prediction of catalytic residues , 2008, Bioinform..

[65]  M. Sternberg,et al.  Insights into protein flexibility: The relationship between normal modes and conformational change upon protein–protein docking , 2008, Proceedings of the National Academy of Sciences.

[66]  Anna R Panchenko,et al.  Coevolution in defining the functional specificity , 2009, Proteins.

[67]  David Baker,et al.  Computation of Conformational Coupling in Allosteric Proteins , 2009, PLoS Comput. Biol..

[68]  R. Nussinov,et al.  The origin of allosteric functional modulation: multiple pre-existing pathways. , 2009, Structure.

[69]  Charalampos G. Kalodimos,et al.  Dynamic activation of an allosteric regulatory protein , 2009, Nature.

[70]  Haim Ashkenazy,et al.  Optimal data collection for correlated mutation analysis , 2009, Proteins.

[71]  Jouhyun Jeon,et al.  Integration of Evolutionary Features for the Identification of Functionally Important Residues in Major Facilitator Superfamily Transporters , 2009, PLoS Comput. Biol..

[72]  R. Ebright,et al.  Structural basis for cAMP-mediated allosteric control of the catabolite activator protein , 2009, Proceedings of the National Academy of Sciences.

[73]  R. Nussinov,et al.  The role of dynamic conformational ensembles in biomolecular recognition. , 2009, Nature chemical biology.

[74]  Olivier Lichtarge,et al.  Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors , 2010, Proceedings of the National Academy of Sciences.

[75]  D. Frishman,et al.  Coevolution predicts direct interactions between mtDNA-encoded and nDNA-encoded subunits of oxidative phosphorylation complex i. , 2010, Journal of molecular biology.

[76]  Cristina Marino Buslje,et al.  Networks of High Mutual Information Define the Structural Proximity of Catalytic Sites: Implications for Catalytic Residue Identification , 2010, PLoS Comput. Biol..

[77]  Christopher A. Brown,et al.  Validation of Coevolving Residue Algorithms via Pipeline Sensitivity Analysis: ELSC and OMES and ZNMI, Oh My! , 2010, PloS one.

[78]  C. Mattos,et al.  Allosteric modulation of Ras positions Q61 for a direct role in catalysis , 2010, Proceedings of the National Academy of Sciences.