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 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 beta-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.
Nishida
M
M
Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, N-12, W-6, Kita-ku, Sapporo 060-0812, CREST, Japan.
Nagata
K
K
Hachimori
Y
Y
Horiuchi
M
M
Ogura
K
K
Mandiyan
V
V
Schlessinger
J
J
Inagaki
F
F
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics; D051380:GRB2 Adaptor Protein; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010455:Peptides / Q000737:chemistry; D011392:Proline / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D010455:Peptides; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011993:Recombinant Fusion Proteins; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D011392:Proline; D066246:ErbB Receptors