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 A. Delaine; Briony E. Forbes; Michael C. Lawrence

doi:10.1016/j.str.2020.05.002

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 A. Delaine, Briony E. Forbes, Michael C. Lawrence

College of Medicine and Public Health

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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.

Original language	English
Pages (from-to)	786-798.e6
Number of pages	20
Journal	STRUCTURE
Volume	28
Issue number	7
DOIs	https://doi.org/10.1016/j.str.2020.05.002
Publication status	Published - 7 Jul 2020

Bibliographical note

This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

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title = "How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor",

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 {\AA}. 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.",

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AU - Croll, Tristan I.

AU - Sandow, Jarrod J.

AU - Webb, Andrew I.

AU - Delaine, Carlie A.

AU - Forbes, Briony E.

AU - Lawrence, Michael C.

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N2 - 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.

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

Abstract

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Keywords

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