Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor

Mol Cell. 2003 Dec;12(6):1379-89. doi: 10.1016/s1097-2765(03)00487-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport*
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Quaternary*
  • Protein Structure, Secondary
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Receptor, Insulin / chemistry*
  • Receptor, Insulin / metabolism*
  • Sequence Alignment
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Proteins
  • SH2B2 protein, human
  • Receptor, Insulin

Associated data

  • PDB/1RPY
  • PDB/1RQQ