title: Structural principles for the multispecificity of small GTP-binding proteins.
abstract: The functional diversity of small GTP-binding proteins (G proteins) and their ability to function as molecular switches are based on their interactions with many different proteins. A wealth of structural data has revealed that their partners are often unrelated to each other in sequence and structure, but their binding sites are in general overlapping, notably at the so-called switch regions, whose conformation is sensitive to the nature of the bound nucleotide. We termed "multispecificity" this unique property of G proteins and investigated its structural principles by a database-implemented comparison of their protein-protein interfaces. Multispecific residues were found to be distributed throughout the G protein surface, with the highest multiplicity at the switch regions, each engaging interactions with 50-80% of the bound partners. Remarkably, residues involved in multiple interactions do not define consensus binding sites where all partners have convergent interactions. Rather, they adapt to multiple stereochemical and structural environments by combining the composite nature of amino acids with structural plasticity. We propose that not only the nucleotide switch but also multispecificity is the hallmark of the G protein module. Thus, G proteins are representative of highly connected proteins located at nodes of protein interactomes, probably the best structurally characterized member of this emerging class of proteins to date. This central functional property is also their Achilles' heal, facilitating their hijacking by pathogens, but may constitute an unexplored advantage in designing or screening novel therapeutic molecules.
authors.affiliation: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Biou
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cherfils
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins