title: Functional specificity conferred by the unique plasticity of fully alpha-helical Ras and Rho GAPs.
abstract: Structural comparisons of the two GTPase activating proteins (GAPs) p120 and p50 in complex with Ras and Rho, respectively, allowed us to decipher the functional role of specific structural features, such as helix alpha8c of p120 and helix A1 of p50, necessary for small GTPase recognition. We identified important residues that may be critical for stabilization of the GAP/GTPase binary complexes. Detection of topohydrophobic positions (positions which are most often occupied by hydrophobic amino acids within a family of protein domains) conserved between the two GAP families led to the characterization of a common flexible four-helix bundle. Altogether, these data are consistent with a rearrangement of several helices around a common core, which strongly supports the assumption that p50 and p120 GAPs derive from a unique fold. Considered as a whole, the remarkable plasticity of GAPs appears to be a means used by nature to accurately confer functional specificity.
authors.affiliation: SmithKline Beecham Laboratoires Pharmaceutiques, 4 rue Chesnay- Beauregard, 35760 Saint-Grégiure, France.
authors.forename: M
authors.initials: M
authors.lastname: Souchet
authors.forename: A
authors.initials: A
authors.lastname: Poupon
authors.forename: I
authors.initials: I
authors.lastname: Callebaut
authors.forename: I
authors.initials: I
authors.lastname: Léger
authors.forename: J
authors.initials: J
authors.lastname: Mornon
authors.forename: A
authors.initials: A
authors.lastname: Bril
authors.forename: T P
authors.initials: TP
authors.lastname: Calmels
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018583:Pliability; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013379:Substrate Specificity; D020729:p120 GTPase Activating Protein / Q000737:chemistry* / Q000378:metabolism*; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D020729:p120 GTPase Activating Protein; C085379:rho GTPase-activating protein; D018631:ras Proteins; D020741:rho GTP-Binding Proteins