Structural Basis for Recruitment of the Adaptor Protein APS to the Activated Insulin Receptor

Junjie Hu, Jun Liu, Rodolfo Ghirlando, Alan R. Saltiel, Stevan R. Hubbard

Research output: Contribution to journalArticle

90 Scopus citations

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 β strand D. This structure provides a molecular visualization of one of the initial downstream recruitment events following insulin activation of its dimeric receptor.

Original languageEnglish (US)
Pages (from-to)1379-1389
Number of pages11
JournalMolecular Cell
Volume12
Issue number6
DOIs
StatePublished - Dec 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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