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PreprintCited by 7Lipid Membrane Structure and BehaviorErythrocyte Function and PathophysiologyIon channel regulation and function

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TMEM63 proteins act as mechanically activated cholesterol modulated lipid scramblases contributing to membrane mechano-resilience

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Lin, Yiechang, Zhou, Zijing, Han, Yaoyao, Cheng, Delfine, Wang, Haoqing, Ju, Arnold Lining, Zhang, Yixiao, Cox, Charles D, Corry, Ben·2025·Nature Communications
DOI 10.1101/2025.07.26.664997PMC PMC13013810

Preprint — published as 10.1038/s41467-026-68919-x · Paper page

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Abstract

OSCA/TMEM63 mechanosensitive ion channels play critical physiological roles in plants and animals. These channels bear structural homology to the dual functional TMEM16 family, and OSCA1.2 was recently shown to form a lipid-lined ion conduction pathway in the open state. This raised the question of whether members of the OSCA/TMEM63 family may also function as mechanically activated lipid scramblases. Using a combination of in vitro and cellular assays with computational techniques, we show that phospholipids can be translocated through the open pores of OSCA1.1/1.2/2.2 and TMEM63A/B proteins, suggesting a dual ion channel and lipid scramblase function for members of this protein family. We characterize the effects of mutating key groove lining residues demonstrating that different residues form bottlenecks for lipids and ions respectively and show that cholesterol inhibits lipid scrambling by stabilizing the closed state and slowing translocation through the open pore. We show that lipid scrambling in TMEM63 proteins can be activated by mechanical forces in the membrane, making these the first identified mechanically activated lipid scramblases. Finally, we demonstrate that this activity is important for the mechanically induced morphological remodeling of biological membranes and the resilience of cells to high mechanical forces.

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Metadata

Authors
Lin, Y., Zhou, Z., Han, Y., Cheng, D., Wang, H., Ju, A. L., Zhang, Y., Cox, C. D., & Corry, B.
Affiliations
  • Australian National University (AU)
  • Victor Chang Cardiac Research Institute (AU)
  • Chinese Academy of Sciences (CN)
  • The University of Sydney (AU)
Corresponding author
  • Zhang, Yixiao
  • Cox, Charles D
  • Corry, Ben
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2025-07-26
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2025.07.26.664997
PMC
PMC13013810
OpenAlex
W7126198019
Cited by
7
References
3
Citations by year
2026: 7
FWCI
14.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Australian Research Council (DP250100893)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Health Sciences › Medicine › Physiology (medical) › Erythrocyte Function and Pathophysiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
lipid scramblase, lipid translocation, mechanical forces
MeSH terms
Anoctamins, Animals, Cell Membrane, Cholesterol, Humans, Phospholipids, Arabidopsis Proteins, Phospholipid Transfer Proteins, HEK293 Cells

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