Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 15, Issue 3, Pages 251-258Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1388
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [P30 CA016087] Funding Source: Medline
- NCRR NIH HHS [S10 RR017990] Funding Source: Medline
- NIDDK NIH HHS [DK052916] Funding Source: Medline
- NINDS NIH HHS [P30 NS050276] Funding Source: Medline
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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.
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