Similar binding sites and different partners: implications to shared proteins in cellular pathways.

We studied a data set of structurally similar interfaces that bind to proteins with different binding-site structures and different functions. Our multipartner protein interface clusters enable us to address questions like: What makes a given site bind different proteins? How similar/different are the interactions? And, what drives the apparently less-specific association? We find that proteins with common binding-site motifs preferentially use conserved interactions at similar interface locations, despite the different partners. Helices are major vehicles for binding different partners, allowing alternate ways to achieve favorable association. The binding sites are characterized by imperfect packing, planar architectures, bridging water molecules, and, on average, smaller size. Interestingly, analysis of the connectivity of these proteins illustrates that they have more interactions with other proteins. These findings are important in predicting "date hubs," if we assume that "date hubs" are shared proteins with binding sites capable of transient binding to multipartners, linking higher-order networks.

[1]  Itay Mayrose,et al.  ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures , 2005, Nucleic Acids Res..

[2]  R. Nussinov,et al.  Favorable scaffolds: proteins with different sequence, structure and function may associate in similar ways. , 2005, Protein engineering, design & selection : PEDS.

[3]  D. Barrell,et al.  The Gene Ontology Annotation (GOA) project: implementation of GO in SWISS-PROT, TrEMBL, and InterPro. , 2003, Genome research.

[4]  A. D. de Vos,et al.  Hematopoietic receptor complexes. , 1996, Annual review of biochemistry.

[5]  Andrej Sali,et al.  Localization of protein‐binding sites within families of proteins , 2005, Protein science : a publication of the Protein Society.

[6]  H. Wolfson,et al.  Protein-protein interfaces: architectures and interactions in protein-protein interfaces and in protein cores. Their similarities and differences. , 1996, Critical reviews in biochemistry and molecular biology.

[7]  H. Wolfson,et al.  A new, structurally nonredundant, diverse data set of protein–protein interfaces and its implications , 2004, Protein science : a publication of the Protein Society.

[8]  Gabriele Ausiello,et al.  MINT: the Molecular INTeraction database , 2006, Nucleic Acids Res..

[9]  S. Vajda,et al.  Anchor residues in protein-protein interactions. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Gary D. Bader,et al.  BIND-a data specification for storing and describing biomolecular interactions, molecular complexes and pathways , 2000, Bioinform..

[11]  Ozlem Keskin,et al.  Protein Interactions and Fluctuations in a Proteomic Network using an Elastic Network Model , 2005, Journal of biomolecular structure & dynamics.

[12]  A. E. Hirsh,et al.  Evolutionary Rate in the Protein Interaction Network , 2002, Science.

[13]  Dinakar M Salunke,et al.  Differential epitope positioning within the germline antibody paratope enhances promiscuity in the primary immune response. , 2006, Immunity.

[14]  Peer Bork,et al.  Shared components of protein complexes--versatile building blocks or biochemical artefacts? , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[15]  O. Lichtarge,et al.  Structural clusters of evolutionary trace residues are statistically significant and common in proteins. , 2002, Journal of molecular biology.

[16]  R. Jernigan,et al.  Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. , 1996, Journal of molecular biology.

[17]  R. Nussinov,et al.  Hot regions in protein--protein interactions: the organization and contribution of structurally conserved hot spot residues. , 2005, Journal of molecular biology.

[18]  Ozlem Keskin,et al.  PRISM: protein interactions by structural matching , 2005, Nucleic Acids Res..

[19]  Eugene V Koonin,et al.  No simple dependence between protein evolution rate and the number of protein-protein interactions: only the most prolific interactors tend to evolve slowly , 2003, BMC Evolutionary Biology.

[20]  O. Schueler‐Furman,et al.  Progress in Modeling of Protein Structures and Interactions , 2005, Science.

[21]  Ioannis Xenarios,et al.  DIP, the Database of Interacting Proteins: a research tool for studying cellular networks of protein interactions , 2002, Nucleic Acids Res..

[22]  R. Nussinov,et al.  Protein–protein interactions: organization, cooperativity and mapping in a bottom-up Systems Biology approach , 2005, Physical biology.

[23]  P. Bork,et al.  Functional organization of the yeast proteome by systematic analysis of protein complexes , 2002, Nature.

[24]  B. Cunningham,et al.  Rational design of receptor-specific variants of human growth hormone. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Mariuzza Multiple paths to multispecificity. , 2006, Immunity.

[26]  Jie Liang,et al.  Protein-protein interactions: hot spots and structurally conserved residues often locate in complemented pockets that pre-organized in the unbound states: implications for docking. , 2004, Journal of molecular biology.

[27]  Michael Schroeder,et al.  Equivalent binding sites reveal convergently evolved interaction motifs , 2006, Bioinform..

[28]  Samara L. Reck-Peterson,et al.  Nuclear actin and actin-related proteins in chromatin remodeling. , 2002, Annual review of biochemistry.

[29]  P. Bork,et al.  Structure-Based Assembly of Protein Complexes in Yeast , 2004, Science.

[30]  Ozlem Keskin,et al.  Prediction of protein-protein interactions by combining structure and sequence conservation in protein interfaces , 2005, Bioinform..

[31]  Thomas E Wales,et al.  Conserved thermodynamic contributions of backbone hydrogen bonds in a protein fold. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[32]  O. Lichtarge,et al.  Character and evolution of protein–protein interfaces , 2005, Physical biology.

[33]  A. Elofsson,et al.  What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae? , 2006, Genome Biology.

[34]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[35]  T. Hughes,et al.  High-definition macromolecular composition of yeast RNA-processing complexes. , 2004, Molecular cell.

[36]  Gail J. Bartlett,et al.  Using a library of structural templates to recognise catalytic sites and explore their evolution in homologous families. , 2005, Journal of molecular biology.

[37]  T. Maniatis,et al.  An extensive network of coupling among gene expression machines , 2002, Nature.

[38]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[39]  W. Delano,et al.  Convergent solutions to binding at a protein-protein interface. , 2000, Science.

[40]  R. Jernigan,et al.  Proteins with similar architecture exhibit similar large-scale dynamic behavior. , 2000, Biophysical journal.

[41]  A G Murzin,et al.  SCOP: a structural classification of proteins database for the investigation of sequences and structures. , 1995, Journal of molecular biology.

[42]  H. Wolfson,et al.  Efficient detection of three-dimensional structural motifs in biological macromolecules by computer vision techniques. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Henikoff,et al.  Amino acid substitution matrices from protein blocks. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  O. Lichtarge,et al.  Evolutionary and structural feedback on selection of sequences for comparative analysis of proteins , 2006, Proteins.

[45]  J M Thornton,et al.  Protein-protein interactions: a review of protein dimer structures. , 1995, Progress in biophysics and molecular biology.

[46]  R. Russell,et al.  The relationship between sequence and interaction divergence in proteins. , 2003, Journal of molecular biology.

[47]  A. Grigoriev On the number of protein-protein interactions in the yeast proteome. , 2003, Nucleic acids research.

[48]  Z. Weng,et al.  Structure, function, and evolution of transient and obligate protein-protein interactions. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Dorothy Beckett,et al.  Functional switches in transcription regulation; molecular mimicry and plasticity in protein-protein interactions. , 2004, Biochemistry.

[50]  Ruth Nussinov,et al.  A method for simultaneous alignment of multiple protein structures , 2004, Proteins.

[51]  C. Adami,et al.  Apparent dependence of protein evolutionary rate on number of interactions is linked to biases in protein–protein interactions data sets , 2003, BMC Evolutionary Biology.

[52]  Daniel R. Caffrey,et al.  Are protein–protein interfaces more conserved in sequence than the rest of the protein surface? , 2004, Protein science : a publication of the Protein Society.

[53]  Lan V. Zhang,et al.  Evidence for dynamically organized modularity in the yeast protein–protein interaction network , 2004, Nature.