2lnw | pdb_00002lnw
Identification and structural basis for a novel interaction between Vav2 and Arap3
Structural highlights
Function[VAV2_HUMAN] Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases. Plays an important role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly (By similarity). [ARAP3_HUMAN] Phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating protein that modulates actin cytoskeleton remodeling by regulating ARF and RHO family members. Is activated by phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) binding. Can be activated by phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding, albeit with lower efficiency. Acts on ARF6, RAC1, RHOA and CDC42. Plays a role in the internalization of anthrax toxin.[1] [2] Publication Abstract from PubMedVav2 is a ubiquitous guanine nucleotide exchange factor (GEF) for the small GTPase Rac1. It regulates processes including cell migration, neuronal development and phagocytosis through interactions with different proteins. In this study, Arap3, a dual GTPase-activating protein (GAP) for RhoA and Arf6, was first identified to be a novel interaction partner for Vav2 both in vitro and in vivo. ITC and NMR chemical shift perturbation experiments demonstrated that Vav2 SH2 domain was able to interact directly with phosphorylated Y1403 and Y1408 within the C-terminal region of Arap3 with high affinities, with the dissociation constants (Kd) of approximately 0.27 and approximately 1.40muM, respectively. In addition, using different phosphotyrosine peptides, the pY +3 specificity of Vav2 SH2 domain was discovered. The solution structures of Vav2 SH2 domain in free and in complex with the phosphotyrosine peptide pY1408 were therefore determined to understand the structural basis of this recognition specificity. Structural analysis revealed that the presence of a Phe residue in the BG loop (BG6) leads to the formation of a shallow hydrophobic pY +3 pocket on the surface of Vav2 SH2 domain, which determines the pY +3 specificity of Vav2 SH2 domain. Identification and structural basis for a novel interaction between Vav2 and Arap3.,Wu B, Wang F, Zhang J, Zhang Z, Qin L, Peng J, Li F, Liu J, Lu G, Gong Q, Yao X, Wu J, Shi Y J Struct Biol. 2012 Oct;180(1):84-95. doi: 10.1016/j.jsb.2012.06.011. Epub 2012, Jun 28. PMID:22750419[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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