De Vecchis, D, Beech, DJ orcid.org/0000-0002-7683-9422 and Kalli, AC orcid.org/0000-0001-7156-9403 (2021) Molecular dynamics simulations of Piezo1 channel opening by increases in membrane tension. Biophysical Journal, 120 (8). P1510-P1521. ISSN 0006-3495
Abstract
Piezo1 is a mechanosensitive channel involved in many cellular functions and responsible for sensing shear stress and pressure forces in cells. Piezo1 has a unique trilobed topology with a curved membrane region in the closed state. It has been suggested that upon activation Piezo1 adopts a flattened conformation, but the molecular and structural changes underpinning the Piezo1 gating and opening mechanisms and how the channel senses forces in the membrane remain elusive. Here, we used molecular dynamics simulations to reveal the structural rearrangements that occur when Piezo1 moves from a closed to an open state in response to increased mechanical tension applied to a model membrane. We find that membrane stretching causes Piezo1 to flatten and expand its blade region, resulting in tilting and lateral movement of the pore-lining transmembrane helices 37 and 38. This is associated with the opening of the channel and movement of lipids out of the pore region. Our results reveal that because of the rather loose packing of Piezo1 pore region, movement of the lipids outside the pore region is critical for the opening of the pore. Our simulations also suggest synchronous flattening of the Piezo1 blades during Piezo1 activation. The flattened structure lifts the C-terminal extracellular domain up, exposing it more to the extracellular space. Our studies support the idea that it is the blade region of Piezo1 that senses tension in the membrane because pore opening failed in the absence of the blades. Additionally, our simulations reveal that upon opening, water molecules occupy lateral fenestrations in the cytosolic region of Piezo1, which might be likely paths for ion permeation. Our results provide a model for how mechanical force opens the Piezo1 channel and thus how it might couple mechanical force to biological response.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 Biophysical Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
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) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number Academy of Medical Sciences Not Known Wellcome Trust 110044/Z/15/Z MRC (Medical Research Council) MR/R01745X/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Feb 2021 14:17 |
Last Modified: | 28 Mar 2022 02:11 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.bpj.2021.02.006 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:170716 |