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Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling.

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posted on 2023-05-23, 01:29 authored by Michael G Sugiyama, Aidan I Brown, Jesus Vega-Lugo, Jazlyn P Borges, Andrew ScottAndrew Scott, Khuloud Jaqaman, Gregory D Fairn, Costin N Antonescu
The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how this may contribute to regulation of EGFR ligand binding is poorly understood. To resolve how EGFR nanoscale compartmentalization gates ligand binding, we developed single-particle tracking methods to track the mobility of ligand-bound and total EGFR, in combination with modeling of EGFR ligand binding. In comparison to unliganded EGFR, ligand-bound EGFR is more confined and distinctly regulated by clathrin and tetraspanin nanodomains. Ligand binding to unliganded EGFR occurs preferentially in tetraspanin nanodomains, and disruption of tetraspanin nanodomains impairs EGFR ligand binding and alters the conformation of the receptor's ectodomain. We thus reveal a mechanism by which EGFR confinement within tetraspanin nanodomains regulates receptor signaling at the level of ligand binding.

Funding

Funding for this research was provided by a Project Grant (PJT-156355) from the Canadian Institutes of Health Research (CIHR) to C.N.A. and G.D.F., and a New Investigator Award from the Canadian Institutes of Health Research (CIHR), Funding from Toronto Metropolitan University, as well as an Early Researcher Award (Ontario Ministry of Research, Innovation and Science) to C.N.A., A.I.B. was supported by a Natural Sciences and Engineering Research Council of Canada Discovery Grant 2021-03431 and start-up funds provided by the Toronto Metropolitan University Faculty of Science. A.M.S. was supported by a National Health and Medical Research Council (NHMRC, Australia) Investigator grant (No. 1177837). G.D.F. holds a Canadian Research Chair in Multiomics of Lipids and Innate Immunity. We thank Austin R. Miranda for providing technical assistance with MATLAB workflow optimization.

History

Publication Date

2023-05-09

Journal

Nature Communications

Volume

14

Issue

1

Article Number

2681

Pagination

17p.

Publisher

Springer Science and Business Media LLC

ISSN

2041-1723

Rights Statement

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.

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