Wu Jinhua, Tseng Yolanda D, Xu Chong-Feng, Neubert Thomas A, White Morris F, Hubbard Stevan R
Structural Biology Program, Kimmel Center for Biology and Medicine of the Skirball Institute, and Department of Pharmacology, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.
Nat Struct Mol Biol. 2008 Mar;15(3):251-8. doi: 10.1038/nsmb.1388. Epub 2008 Feb 17.
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.
胰岛素受体底物1和2（IRS1和-2）是介导胰岛素和胰岛素样生长因子1的代谢及促有丝分裂作用的关键衔接蛋白。这些蛋白质由一个普列克底物蛋白同源结构域、一个磷酸酪氨酸结合结构域以及一个包含众多酪氨酸、丝氨酸和苏氨酸磷酸化位点的C端区域组成。以往的酵母双杂交研究鉴定出了IRS2特有的一个区域，称为激酶调节环结合（KRLB）区域，该区域与胰岛素受体的酪氨酸激酶结构域相互作用。在此，我们展示了胰岛素受体激酶与来自KRLB区域的一个15残基肽段形成复合物的晶体结构。在该结构中，IRS2的这一片段结合在激酶活性位点，酪氨酸628（Tyr628）处于可被磷酸化的位置。尽管Tyr628被胰岛素受体磷酸化，但其催化周转较差，导致激酶抑制。我们的研究表明，KRLB区域的功能是限制IRS2的酪氨酸磷酸化。
