Premium
Novel recognition mode between Vav and Grb2 SH3 domains
Author(s) -
Nishida Motohiko,
Nagata Koji,
Hachimori Yukiko,
Horiuchi Masataka,
Ogura Kenji,
Mandiyan Valsan,
Schlessinger Joseph,
Inagaki Fuyuhiko
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.12.2995
Subject(s) - biology , sh3 domain , guanine nucleotide exchange factor , grb2 , binding site , plasma protein binding , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , biophysics , biochemistry , signal transduction
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 Src‐homology 3 (SH3) domain (GrbS) and the N‐terminal SH3 domain of Vav (VavS). 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 proline‐rich peptides is blocked by its own RT loop. One of the ends of the VavS β‐barrel forms a concave hydrophobic surface. The GrbS components make a contiguous complementary interface with the VavS surface. The binding site of GrbS for VavS partially overlaps with the canonical binding site for proline‐rich peptides, but is definitely different. Mutations at the interface caused a decrease in the binding affinity of VavS for GrbS by 4‐ to 40‐fold. The structure reveals how GrbS discriminates VavS specifically from other signaling molecules without binding to the proline‐rich motif.