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Title: Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling.
Austin Authors: Sugiyama, Michael G;Brown, Aidan I;Vega-Lugo, Jesus;Borges, Jazlyn P;Scott, Andrew M ;Jaqaman, Khuloud;Fairn, Gregory D;Antonescu, Costin N
Affiliation: Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON, Canada.
Department of Physics, Toronto Metropolitan University, Toronto, ON, Canada.
Department of Biophysics, UT Southwestern Medical Center, Dallas, TX, USA.
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.
Olivia Newton-John Cancer Research Institute
Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA.
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Issue Date: 9-May-2023
Date: 2023
Publication information: Nature Communications 2023
Abstract: 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.
DOI: 10.1038/s41467-023-38390-z
ORCID: 0000-0002-3443-6772
Journal: Nature Communications
Start page: 2681
PubMed URL: 37160944
ISSN: 2041-1723
Type: Journal Article
Appears in Collections:Journal articles

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