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Direct observation of the conformational states of PIEZO1

Eric M. Mulhall, Anant Gharpure, Rachel M. Lee, Adrienne E. Dubin, Jesse S. Aaron, Kara L. Marshall, Kathryn R. Spencer, Michael A. Reiche, Scott C. Henderson, Teng-Leong Chew and Ardem Patapoutian ()
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Eric M. Mulhall: Dorris Neuroscience Center, Scripps Research
Anant Gharpure: Dorris Neuroscience Center, Scripps Research
Rachel M. Lee: Advanced Imaging Center, Howard Hughes Medical Institute Janelia Research Campus
Adrienne E. Dubin: Dorris Neuroscience Center, Scripps Research
Jesse S. Aaron: Advanced Imaging Center, Howard Hughes Medical Institute Janelia Research Campus
Kara L. Marshall: Dorris Neuroscience Center, Scripps Research
Kathryn R. Spencer: Dorris Neuroscience Center, Scripps Research
Michael A. Reiche: Advanced Imaging Center, Howard Hughes Medical Institute Janelia Research Campus
Scott C. Henderson: Scripps Research
Teng-Leong Chew: Advanced Imaging Center, Howard Hughes Medical Institute Janelia Research Campus
Ardem Patapoutian: Dorris Neuroscience Center, Scripps Research

Nature, 2023, vol. 620, issue 7976, 1117-1125

Abstract: Abstract PIEZOs are mechanosensitive ion channels that convert force into chemoelectric signals1,2 and have essential roles in diverse physiological settings3. In vitro studies have proposed that PIEZO channels transduce mechanical force through the deformation of extensive blades of transmembrane domains emanating from a central ion-conducting pore4–8. However, little is known about how these channels interact with their native environment and which molecular movements underlie activation. Here we directly observe the conformational dynamics of the blades of individual PIEZO1 molecules in a cell using nanoscopic fluorescence imaging. Compared with previous structural models of PIEZO1, we show that the blades are significantly expanded at rest by the bending stress exerted by the plasma membrane. The degree of expansion varies dramatically along the length of the blade, where decreased binding strength between subdomains can explain increased flexibility of the distal blade. Using chemical and mechanical modulators of PIEZO1, we show that blade expansion and channel activation are correlated. Our findings begin to uncover how PIEZO1 is activated in a native environment. More generally, as we reliably detect conformational shifts of single nanometres from populations of channels, we expect that this approach will serve as a framework for the structural analysis of membrane proteins through nanoscopic imaging.

Date: 2023
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DOI: 10.1038/s41586-023-06427-4

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