Novel recognition mode between Vav and Grb2 SH3 domains

Vav is a guanine nucleotide exchange factor for the Rho/Rac family that is expressed exclusively in hematopoietic cells. Growth factor receptor-bound protein 2 (Grb2) has been proposed to play important roles in the membrane localization and activation of Vav through dimerization of its C-terminal S rc-homology 3 (SH3) domain (GrbS) and the N-terminal SH3 domain of Vav (Vav S). The crystal structure of VavS complexed with GrbS has been solved. VavS is distinct from other SH3 domain proteins in that its binding site for pr oline-rich peptides is blocked by its own RT loop. One of the ends of the V avS beta -barrel Terms a concave hydrophobic surface. The GrbS components m ake a contiguous complementary interface with the VavS surface. The binding site of GrbS for VavS partially overlaps with the canonical binding site f or proline-rich peptides, but is definitely different. Mutations at the int erface caused a decrease in the binding affinity of VavS for GrbS by 4- to 40-fold. The structure reveals how GrbS discriminates VavS specifically fro m other signaling molecules without binding to the proline-rich motif.