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Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14.

ABSTRACT: Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family. Previous studies have demonstrated that Grb14 is a tissue-specific negative regulator of insulin receptor signaling and that inhibition is mediated by the BPS region. We have determined the crystal structure of the Grb14 BPS region in complex with the tyrosine kinase domain of the insulin receptor. The structure reveals that the N-terminal portion of the BPS region binds as a pseudosubstrate inhibitor in the substrate peptide binding groove of the kinase. Together with the crystal structure of the SH2 domain, we present a model for the interaction of Grb14 with the insulin receptor, which indicates how Grb14 functions as a selective protein inhibitor of insulin signaling.

SUBMITTER: Depetris RS

PROVIDER: S-EPMC4526137 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

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Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14.

Depetris Rafael S RS Hu Junjie J Gimpelevich Ilana I Holt Lowenna J LJ Daly Roger J RJ Hubbard Stevan R SR

Molecular cell 20051001 2

Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family. Previous studies have demonstrated that Grb14 is a tissue-specific negative regulator of insulin receptor signaling and that inhibition is mediated by the BPS region. We have determined the crystal structure of the Grb14 BPS region in compl ...[more]

PMID: 16246733

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