Structural and functional basis of mechanosensitive TMEM63 channelopathies

Wang Zheng¹, Augustus J Lowry², Harper E Smith³, Jiale Xie⁴, Shaun Rawson⁵, Chen Wang⁴, Jin Ou⁶, Marcos Sotomayor⁷, Tian-Min Fu⁴, Huanghe Yang⁸, Jeffrey R Holt⁹

Affiliations

¹ Departments of Otolaryngology & Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: wzheng86@wisc.edu.
² Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
³ Biophysics Program, The Ohio State University, Columbus, OH 43210, USA; Center for Mechanical Excitability, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
⁴ Department of Pathology, UMass Chan Medical School, Worcester, MA 01655, USA.
⁵ Harvard Cryo-Electron Microscopy Center for Structural Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Center for Mechanical Excitability, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
⁸ Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
⁹ Departments of Otolaryngology & Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: jeffrey.holt@childrens.harvard.edu.

PMID: 40480214
PMCID: PMC12445292 (available on 2026-06-05)
DOI: 10.1016/j.neuron.2025.05.009

Structural and functional basis of mechanosensitive TMEM63 channelopathies

Wang Zheng et al. Neuron. 2025.

. 2025 Aug 6;113(15):2474-2489.e5.

doi: 10.1016/j.neuron.2025.05.009. Epub 2025 Jun 5.

Authors

Wang Zheng¹, Augustus J Lowry², Harper E Smith³, Jiale Xie⁴, Shaun Rawson⁵, Chen Wang⁴, Jin Ou⁶, Marcos Sotomayor⁷, Tian-Min Fu⁴, Huanghe Yang⁸, Jeffrey R Holt⁹

Affiliations

¹ Departments of Otolaryngology & Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: wzheng86@wisc.edu.
² Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
³ Biophysics Program, The Ohio State University, Columbus, OH 43210, USA; Center for Mechanical Excitability, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
⁴ Department of Pathology, UMass Chan Medical School, Worcester, MA 01655, USA.
⁵ Harvard Cryo-Electron Microscopy Center for Structural Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Center for Mechanical Excitability, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
⁸ Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
⁹ Departments of Otolaryngology & Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: jeffrey.holt@childrens.harvard.edu.

PMID: 40480214
PMCID: PMC12445292 (available on 2026-06-05)
DOI: 10.1016/j.neuron.2025.05.009

Abstract

TMEM63A, -B, and -C constitute a mammalian family of mechanosensitive ion channels that are mutated in neurodevelopmental disorders. The molecular mechanisms underlying TMEM63 activation by force and the impact of disease-associated mutations have not been clarified. Here, we elucidate the structural and functional bases of a prevalent TMEM63B mutation p.V44M. We first found that TMEM63B p.V44M and the homologous TMEM63A p.V53M are gain-of-function mutations that do not enhance channel activity but instead evoke constitutive lipid scramblase activity. We then solved TMEM63A p.V53M mutant structures in both closed and lipid-open states, which revealed major rearrangements of pore-lining helices, creating a lateral cleft across the membrane. Simulation studies revealed lipid scrambling through this cleft. The structural rearrangements were triggered by disruption of a surface-proximal hydrophobic latch, a putative force-sensing module that includes a cluster of disease mutation sites. Our findings provide mechanistic insight into TMEM63 channelopathies and suggest a possible force-sensing mechanism.

Keywords: TMC; TMEM16; TMEM63; disease mutation; force sensing; hydrophobic latch; ion channel; lipid cleft; mechanosensitive; neurodevelopmental disorder; scramblase.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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Structural and functional basis of mechanosensitive TMEM63 channelopathies

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Structural and functional basis of mechanosensitive TMEM63 channelopathies

Authors

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Abstract

Conflict of interest statement

References

MeSH terms

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Grants and funding