Structural and Biochemical Characterization of the KRLB Region in Insulin Receptor Substrate-2

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Nature Structural and Molecular Biology

DOI:https://doi.org/10.1038/nsmb.1388· OSTI ID:959846

Wu, J; Tseng, Y; Xu, C; Neubert, T; White, M; Hubbard, S

Insulin receptor substrates 1 and 2 (IRS1 and -2) are crucial adaptor proteins in mediating the metabolic and mitogenic effects of insulin and insulin-like growth factor 1. These proteins consist of a pleckstrin homology domain, a phosphotyrosine binding domain and a C-terminal region containing numerous sites of tyrosine, serine and threonine phosphorylation. Previous yeast two-hybrid studies identified a region unique to IRS2, termed the kinase regulatory-loop binding (KRLB) region, which interacts with the tyrosine kinase domain of the insulin receptor. Here we present the crystal structure of the insulin receptor kinase in complex with a 15-residue peptide from the KRLB region. In the structure, this segment of IRS2 is bound in the kinase active site with Tyr628 positioned for phosphorylation. Although Tyr628 was phosphorylated by the insulin receptor, its catalytic turnover was poor, resulting in kinase inhibition. Our studies indicate that the KRLB region functions to limit tyrosine phosphorylation of IRS2.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959846
• Report Number(s): BNL--82832-2009-JA
• Journal Information: Nature Structural and Molecular Biology, Journal Name: Nature Structural and Molecular Biology Journal Issue: 3 Vol. 15
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
GROWTH FACTORS
INSULIN
PEPTIDES
PHOSPHORYLATION
PHOSPHOTRANSFERASES
PROTEINS
RECEPTORS
SERINE
SUBSTRATES
THREONINE
TYROSINE
YEASTS
national synchrotron light source