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

Rafael S Depetris, Junjie Hu, Ilana Gimpelevich, Loweanna J Holt, Roger John Daly, Stevan R Hubbard

Research output: Contribution to journalArticleResearchpeer-review

84 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)325 - 333
Number of pages9
JournalMolecular Cell
Volume20
Issue number2
DOIs
Publication statusPublished - 2005
Externally publishedYes

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