Structural basis for dimerization of the Grb10 Src homology 2 domain. Implications for ligand specificity.

Grb7, Grb10, and Grb14 are members of a distinct family of adapter proteins that interact with various receptor tyrosine kinases upon receptor activation. Proteins in this family contain several modular signaling domains including a pleckstrin homology (PH) domain, a BPS (between PH and SH2) domain, and a C-terminal Src homology ...
2 (SH2) domain. Although SH2 domains are typically monomeric, we show that the Grb10 SH2 domain and also full-length Grb10 gamma are dimeric in solution under physiologic conditions. The crystal structure of the Grb10 SH2 domain at 1.65-A resolution reveals a non-covalent dimer whose interface comprises residues within and flanking the C-terminal alpha helix, which are conserved in the Grb7/Grb10/Grb14 family but not in other SH2 domains. Val-522 in the BG loop (BG3) and Asp-500 in the EF loop (EF1) are positioned to interfere with the binding of the P+3 residue of a phosphopeptide ligand. These structural features of the Grb10 SH2 domain will favor binding of dimeric, turn-containing phosphotyrosine sequences, such as the phosphorylated activation loops in the two beta subunits of the insulin and insulin-like growth factor-1 receptors. Moreover, the structure suggests the mechanism by which the Grb7 SH2 domain binds selectively to pTyr-1139 (pYVNQ) in Her2, which along with Grb7 is co-amplified in human breast cancers.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Binding Sites, Crystallography, X-Ray, Dimerization, ErbB Receptors, GRB10 Adaptor Protein, GRB7 Adaptor Protein, Humans, Ligands, Molecular Sequence Data, Peptide Fragments, Protein Conformation, Protein Structure, Secondary, Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Solutions, Substrate Specificity, src Homology Domains
J. Biol. Chem.
Date: Apr. 11, 2003
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