Structural Basis for Inhibition of the Insulin Receptor by the Adaptor Protein Grb14

Journal Article · Sat Jan 01 04:00:00 EST 2005 · Mol. Cell

DOI:https://doi.org/10.1016/j.molcel.2005.09.001· OSTI ID:913698

Depetris, R; Hu, J; Gimpelevich, I; Holt, L; Daly, R; Hubbard, S

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 {approx}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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 913698
• Report Number(s): BNL--78266-2007-JA
• Journal Information: Mol. Cell, Journal Name: Mol. Cell Journal Issue: 2 Vol. 20
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
INSULIN
PEPTIDES
PHOSPHOTRANSFERASES
PROTEINS
RESIDUES
SUBSTRATES
TYROSINE
national synchrotron light source