title: The C-terminal SH3 domain contributes to the intramolecular inhibition of Vav family proteins.
abstract: Vav proteins are phosphorylation-dependent guanine nucleotide exchange factors (GEFs) that catalyze the activation of members of the Rho family of guanosine triphosphatases (GTPases). The current regulatory model holds that the nonphosphorylated, catalytically inactive state of these GEFs is maintained by intramolecular interactions among the amino-terminal domains and the central catalytic core, which block the binding of Vav proteins to GTPases. We showed that this autoinhibition is mechanistically more complex, also involving the bivalent association of the carboxyl-terminal Src homology 3 (SH3) region of Vav with its catalytic and pleckstrin homology (PH) domains. Such interactions occurred through proline-rich region-independent mechanisms. Full release from this double-locked state required synergistic weakening effects from multiple phosphorylated tyrosine residues, thus providing an optimized system to generate gradients of Vav GEF activity depending on upstream signaling inputs. This mechanism is shared by mammalian and Drosophila melanogaster Vav proteins, suggesting that it may be a common regulatory feature for this protein family.
authors.affiliation: 1Centro de Investigación del Cáncer, Campus Unamuno, E37007 Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Barreira
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fabbiano
authors.forename: José R
authors.initials: JR
authors.lastname: Couceiro
authors.forename: Eva
authors.initials: E
authors.lastname: Torreira
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Martínez-Torrecuadrada
authors.forename: Guillermo
authors.initials: G
authors.lastname: Montoya
authors.forename: Oscar
authors.initials: O
authors.lastname: Llorca
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
mesh_terms: D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D004331:Drosophila melanogaster / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D019169:Jurkat Cells; D051379:Mice; D005810:Multigene Family; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry; D051567:Proto-Oncogene Proteins c-vav / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains
chemical_list: D051567:Proto-Oncogene Proteins c-vav; D014443:Tyrosine; D011392:Proline; D020558:GTP Phosphohydrolases