Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON, Canada.
Department of Physics, Toronto Metropolitan University, Toronto, ON, Canada.
Nat Commun. 2023 May 9;14(1):2681. doi: 10.1038/s41467-023-38390-z.
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.
表皮生长因子受体 (EGFR) 是细胞生理学的中央调节因子。EGFR 通过配体结合而被激活，触发受体二聚化、激酶活性的激活和细胞内信号转导。EGFR 短暂地局限于各种质膜纳米域内，但这种情况如何有助于调节 EGFR 配体结合仍知之甚少。为了解 EGFR 纳米级区室化如何调控配体结合，我们开发了单颗粒跟踪方法来跟踪配体结合和总 EGFR 的迁移率，同时对 EGFR 配体结合进行建模。与未结合配体的 EGFR 相比，结合配体的 EGFR 受到网格蛋白和四跨膜蛋白纳米域的限制更为明显，且受到明显的调控。配体优先在四跨膜蛋白纳米域中与未结合配体的 EGFR 结合，破坏四跨膜蛋白纳米域会损害 EGFR 配体结合并改变受体胞外结构域的构象。因此，我们揭示了一种机制，即 EGFR 在四跨膜蛋白纳米域内的限制可在配体结合水平上调节受体信号。
