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PMID: 11406576 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Novel recognition mode between Vav and Grb2 SH3 domains.

The EMBO journal ·Vol. 20 ·No. 12 ·2001-06-15 ·Pages 2995-3007

Nishida M, Nagata K, Hachimori Y, Horiuchi M, Ogura K, Mandiyan V, Schlessinger J, Inagaki F

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing Amino Acid Sequence Animals Cell Cycle Proteins Crystallography, X-Ray ErbB Receptors/chemistry,genetics GRB2 Adaptor Protein Guanine Nucleotide Exchange Factors/chemistry,genetics Humans Mice Models, Molecular Molecular Sequence Data Mutagenesis Peptides/chemistry Proline/chemistry,genetics Protein Structure, Secondary Proteins/chemistry,genetics Proto-Oncogene Proteins/chemistry,genetics Proto-Oncogene Proteins c-vav Recombinant Fusion Proteins/chemistry,genetics src Homology Domains
Chemicals
Adaptor Proteins, Signal Transducing Cell Cycle Proteins GRB2 Adaptor Protein GRB2 protein, human Grb2 protein, mouse Guanine Nucleotide Exchange Factors Peptides Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-vav Recombinant Fusion Proteins VAV1 protein, human Vav1 protein, mouse Proline ErbB Receptors
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Nishida 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
Hachimori Y
Horiuchi M
Ogura K
Mandiyan V
Schlessinger J
Inagaki F
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/20.12.2995
Published
2001-06-15
Pages
2995-3007
Language
English
Region
England
NLM ID
8208664
PMCID
PMC150196
Subset
IM
Databases
PDB
1GCP, 1GCQ
External Links
PubMed source DOI: 10.1093/emboj/20.12.2995 PMC Full Text View journal details
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