How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor

Structure. 2020 Jul 7;28(7):786-798.e6. doi: 10.1016/j.str.2020.05.002. Epub 2020 May 26.

Abstract

Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth factor II signaling via IGF-1R, despite the affinity of insulin-like growth factor II for IGF-1R being within an order of magnitude of that of insulin-like growth factor I. Here, we describe the cryoelectron microscopy structure of insulin-like growth factor II bound to a leucine-zipper-stabilized IGF-1R ectodomain, determined in two conformations to a maximum average resolution of 3.2 Å. The two conformations differ in the relative separation of their respective points of membrane entry, and comparison with the structure of insulin-like growth factor I bound to IGF-1R reveals long-suspected differences in the way in which the critical C domain of the respective growth factors interact with IGF-1R.

Keywords: cryoelectron microscopy; insulin-like growth factor I; insulin-like growth factor II; leucine zipper; single-particle 3D reconstruction; type 1 insulin-like growth factor receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cryoelectron Microscopy
  • Humans
  • Insulin-Like Growth Factor II / chemistry*
  • Insulin-Like Growth Factor II / metabolism
  • Mice
  • Molecular Docking Simulation
  • Protein Binding
  • Receptor, IGF Type 1 / chemistry*
  • Receptor, IGF Type 1 / metabolism

Substances

  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1