Smith, K.A., Chuntharpursat, E., Povstyan, O.V. et al. (8 more authors) (2025) Regulation of PIEZO1 channel force sensitivity by interblade handshaking. Science Advances, 11 (24). eadt7046. ISSN: 2375-2548
Abstract
PIEZOs form trimeric calcium-permeable nonselective cationic channels that serve mechanical sensing needs across eukaryotic biology. Forces act on the channels by causing their curved blades to flatten and decompact, leading to an activated state, but it is unclear how this is regulated to enable the channels to adapt to different contexts. To identify potential mechanisms, we performed coarse-grained and all-atom molecular dynamics simulations on human PIEZO1. We observed an interblade handshake interaction mediated by basic amino acid residues in two flexible helices coordinated with regulated anionic lipid phosphatidylinositol 4,5-bisphosphate. The interaction determined the resting configuration of the channel, blade curvature, compactness, and ion pore structure. In experiments, disruption of the handshake by neutralization of helix amino acids or phosphatidylinositol 4,5-bisphosphate depletion increased the channel’s sensitivity to membrane tension. Structural and amino acid sequence analysis for multiple PIEZOs predicted helix amino acid arrangements for varied handshaking intensity. We suggest a dynamic interaction in PIEZO channels that regulates force sensitivity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation PG/21/10595 British Heart Foundation PG/21/10515 |
Depositing User: | Symplectic Publications |
Date Deposited: | 02 May 2025 09:28 |
Last Modified: | 06 Aug 2025 14:35 |
Status: | Published |
Publisher: | American Association for the Advancement of Science |
Identification Number: | 10.1126/sciadv.adt7046 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:226098 |