Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States
Patrick O Byrne
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States
Mary Katherine Connacher
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
Zhihong Wang
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
Alexander Ramek
DE Shaw Research, New York, United States
Sarvenaz Sarabipour
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, United States
Yibing Shan
DE Shaw Research, New York, United States
David E Shaw
DE Shaw Research, New York, United States; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
Kalina Hristova
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, United States
Philip A Cole
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
Daniel J Leahy
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
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.
