title: Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor.
abstract: Tyrosine 984 in the juxtamembrane region of the insulin receptor, between the transmembrane helix and the cytoplasmic tyrosine kinase domain, is conserved among all insulin receptor-like proteins from hydra to humans. Crystallographic studies of the tyrosine kinase domain and proximal juxtamembrane region reveal that Tyr-984 interacts with several other conserved residues in the N-terminal lobe of the kinase domain, stabilizing a catalytically nonproductive position of alpha-helix C. Steady-state kinetics measurements on the soluble kinase domain demonstrate that replacement of Tyr-984 with phenylalanine results in a 4-fold increase in kcat in the unphosphorylated (basal state) enzyme. Moreover, mutation of Tyr-984 in the full-length insulin receptor results in significantly elevated receptor phosphorylation levels in cells, both in the absence of insulin and following insulin stimulation. These data demonstrate that Tyr-984 plays an important structural role in maintaining the quiescent, basal state of the insulin receptor. In addition, the structural studies suggest a possible target site for small molecule activators of the insulin receptor, with potential use in the treatment of noninsulin-dependent diabetes mellitus.
authors.affiliation: Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Shiqing
authors.initials: S
authors.lastname: Li
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Covino
authors.forename: Evan G
authors.initials: EG
authors.lastname: Stein
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Till
authors.forename: Stevan R
authors.initials: SR
authors.lastname: Hubbard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D014443:Tyrosine; D011972:Receptor, Insulin