title: Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor.
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.
authors.affiliation: Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Hu
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Ghirlando
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.forename: Stevan R
authors.initials: SR
authors.lastname: Hubbard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D011972:Receptor, Insulin / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D011506:Proteins; C107249:SH2B2 protein, human; D011972:Receptor, Insulin