How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor
Yibin Xu, Nicholas S. Kirk, Hariprasad Venugopal, Mai B. Margetts, Tristan I. Croll, Jarrod J. Sandow, Andrew I. Webb, Carlie Delaine, Briony E. Forbes, Michael C. Lawrence
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.