Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor.
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Hu J, Liu J, Ghirlando R, Saltiel AR, Hubbard SR
Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor.
Mol Cell. 2003 Dec;12(6):1379-89.
- PubMed ID
- 14690593 [ View in PubMed]
- Abstract
The adaptor protein APS is a substrate of the insulin receptor and couples receptor activation with phosphorylation of Cbl to facilitate glucose uptake. The interaction with the activated insulin receptor is mediated by the Src homology 2 (SH2) domain of APS. Here, we present the crystal structure of the APS SH2 domain in complex with the phosphorylated tyrosine kinase domain of the insulin receptor. The structure reveals a novel dimeric configuration of the APS SH2 domain, wherein the C-terminal half of each protomer is structurally divergent from conventional, monomeric SH2 domains. The APS SH2 dimer engages two kinase molecules, with pTyr-1158 of the kinase activation loop bound in the canonical phosphotyrosine binding pocket of the SH2 domain and a second phosphotyrosine, pTyr-1162, coordinated by two lysine residues in beta strand D. This structure provides a molecular visualization of one of the initial downstream recruitment events following insulin activation of its dimeric receptor.