Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch
Author
Gordon, Wendy R.
Miles, Laura J.
Huang, Jiuhong
Tiyanont, Kittichoat
McArthur, Debbie G.
Published Version
https://doi.org/10.1016/j.devcel.2015.05.004Metadata
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Gordon, Wendy R., Brandon Zimmerman, Li He, Laura J. Miles, Jiuhong Huang, Kittichoat Tiyanont, Debbie G. McArthur et al. "Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch." Developmental Cell 33, no. 6 (2015): 729-736. DOI: 10.1016/j.devcel.2015.05.004Abstract
Ligands stimulate Notch receptors by inducing regulated intramembrane proteolysis (RIP) to produce a transcriptional effector. Notch activation requires unmasking of a metalloprotease cleavage site remote from the site of ligand binding, raising the question of how proteolytic sensitivity is achieved. Here, we show that application of physiologically relevant forces to the regulatory switch results in sensitivity to metalloprotease cleavage, and that bound ligands induce Notch signal transduction in cells only in the presence of applied mechanical force. Synthetic receptor-ligand systems that remove the native ligand-receptor interaction also activate Notch by inducing proteolysis of the regulatory switch. Together, these studies show that mechanical force exerted by signal-sending cells is required for ligand-induced Notch activation, and establish that force-induced proteolysis can act as a mechanism of cellular mechanotransduction.Other Sources
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481192/Terms of Use
This article is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#OAPCitable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372440
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