Journal article

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 Croll, Jarrod J Sandow, Andrew Webb, Carlie A Delaine, Briony E Forbes, Michael C Lawrence

Structure | CELL PRESS | Published : 2020

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 com..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Wellcome Trust


Awarded by National Institutes of Health


Funding Acknowledgements

The authors acknowledge use of facilities within theMonashRamaciottiCryoEM platform. M.C.L. acknowledges financial support from the Australian National Health and Medical Research Council (NHMRC) project grant APP1128553; his institute receives Victorian State Government Operational Infrastructure support and funding from the Australian NHMRC Independent Research Institutes Infrastructure support scheme. T.I.C. is supported by the Wellcome Trust Principal ResearchFellowship of Prof. RandyRead(grant number 209407/Z/17/Z). The authors thank Prof. Ken Siddle (University ofCambridge, England) for providing the hybridomas expressing mAb 24-60, and Dr. Oliver Clarke (Columbia University, USA) for advice regarding cryo-EM software. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, andInformatics at theUniversityofCalifornia, SanFrancisco, with support fromNational Institutes ofHealthR01-GM129325 and theOffice of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. This paper is dedicated to our late colleague and mentor, Dr. Colin Ward, who initiated our structural studies of IGF-1R.