User:Olivier Laprevote/Sandbox 1

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Function

Guanine nucleotide exchange factor (GEF) of the Rho/Rac GTPases ^[3], including Ras and Cdc42.

Disease

Relevance

Structural highlights

The Vav1 are (from N ter to C ter): a calponin-homology (CH) domain, an acidic (Ac) domain, a DBL-homology (DH) domain also known as a rhoGEF domain, a pleckstrin-homology (PH) domain, a phorbol esters/diacylglycerol binding (C1) domain also called Zinc-finger domain and Src-homology (SH) 3 and 2 domains. ^{[4] [5]}

(residues 1 - 119): When the CH domain is deleted, Vav has a phosphorylation-independant GEF activity. Studies on Vav3 implies that CH plays a role in auto-inhibition of Vav via its interactions with the (between the residue 49 in CH and 181 in Ac), DH and regions (C1 interacts with L101 and L104 of CH). The contacts with DH and C1 seem passively driven by the interactions between Ac and CH, though. ^[6]

(residues 134 - 187): contains the Tyrosine (Y174) which activates Vav when phosphorylated. ^[7]

(residues 194 - 373): present in every Rho/rac GEF, it is the active site of the GTP exchange with the C1 domain in Vav and it promotes the binding to rho GTPase with the help of the C1 domain. It always has a PH domain just after its C terminal.^[8]

(residues 402 - 504): point mutation in it don't change the exchange activity of Vav, so it isn't directly involved in its GEF function ^[9]. But the presence of phosphatidylinositol-4,5-bisphosphate (PIP 2) inhibits 90% of Vav activity while phosphatidylinositol-3,4,5-trisphosphate doubles it. It is very likely that the interactions between these lipids and Vav happen on the PH domain, as it is commonly the case on other proteins with this region. It should be noted that the activation of Vav is made in parallel of the one of PI3-kinase in TCR and BCR pathway. ^[10]

phorbol esters/diacylglycerol binding (C1) domain (508 - 584) : has a cooperative action with the DH domain to bind to the rho GTPase and to promote the GEF activity of Vav.