title: The insulin and IGF1 receptor kinase domains are functional dimers in the activated state.
abstract: The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are highly related receptor tyrosine kinases with a disulfide-linked homodimeric architecture. Ligand binding to the receptor ectodomain triggers tyrosine autophosphorylation of the cytoplasmic domains, which stimulates catalytic activity and creates recruitment sites for downstream signalling proteins. Whether the two phosphorylated tyrosine kinase domains within the receptor dimer function independently or cooperatively to phosphorylate protein substrates is not known. Here we provide crystallographic, biophysical and biochemical evidence demonstrating that the phosphorylated kinase domains of IR and IGF1R form a specific dimeric arrangement involving an exchange of the juxtamembrane region proximal to the kinase domain. In this dimer, the active position of α-helix C in the kinase N lobe is stabilized, which promotes downstream substrate phosphorylation. These studies afford a novel strategy for the design of small-molecule IR agonists as potential therapeutic agents for type 2 diabetes.
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: M Zulema
authors.initials: MZ
authors.lastname: Cabail
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Shiqing
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lemmon
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bowen
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Stevan R
authors.initials: SR
authors.lastname: Hubbard
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: W Todd
authors.initials: WT
authors.lastname: Miller
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics; D016367:Baculoviridae / Q000235:genetics; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000737:chemistry*; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000737:chemistry* / Q000235:genetics; D017451:Receptors, Somatomedin / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D061987:Sf9 Cells; D018411:Spodoptera; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D015703:Antigens, CD; C000597236:IGF1R protein, human; D007328:Insulin; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins; D053835:Unilamellar Liposomes; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin