title: How IGF-1 activates its receptor.
abstract: The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kavran
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Jacqueline M
authors.identifier: http://orcid.org/0000-0001-9032-5359
authors.initials: JM
authors.lastname: McCabe
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Byrne
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Mary Katherine
authors.initials: MK
authors.lastname: Connacher
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.|Department of Chemistry and Biochemistry, University of the Sciences, Philadelphia, United States.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: DE Shaw Research, New York, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ramek
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, United States.
authors.forename: Sarvenaz
authors.initials: S
authors.lastname: Sarabipour
authors.affiliation: DE Shaw Research, New York, United States.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Shan
authors.affiliation: DE Shaw Research, New York, United States.|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, United States.
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Leahy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: FRET; IGF1 receptor; biochemistry; biophysics; human; kinetics; mechanism; structural biology