ArticleNeuron2025
Structural and functional basis of mechanosensitive TMEM63 channelopathies.
Article in Neuron, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- Lipid flip-flop in biological membranes: through the lens of TMEM16F.Physiological reviews · 2026Review
- A TMEM63B variant with enhanced mechanosensitive channel activity and acquired lipid scramblase function.The Journal of general physiology · 2026Article
- Bayesian-Steered Structure Prediction of Mechanical Biomolecules Using Twisted Diffusion.bioRxiv : the preprint server for biology · 2026Article
- TMEM63 proteins act as mechanically activated cholesterol modulated lipid scramblases contributing to membrane mechano-resilience.Nature communications · 2026Article
- From plasma membrane to lysosomes: expanding roles of TMEM63/OSCA channels in mechanosensation and intracellular signaling.Frontiers in pharmacology · 2026Review
- Mechanosensitive TMEM63 Ion Channels: Structure, Gating Mechanism, and Emerging Physiological and Pathological Roles.Results and problems in cell differentiation · 2026Review
- Targeting Tmem63b and Piezo2 in C-fiber low-threshold mechanoreceptors: Limitation of Vglut3-IRES-Cre.Biophysical journal · 2025Article
- Glial Ion Channels in Myelin Pathophysiology: Insights from Leukodystrophies.Life (Basel, Switzerland) · 2025Review
- Groove architecture controls lipid scrambling in simulations of protein and model systems.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
11 authors.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.