9N95

Human TMEM63A mutant V53M closed state

Summary for 9N95

• Entry DOI: 10.2210/pdb9n95/pdb
• EMDB information: 49160
• Descriptor: CSC1-like protein 1 (1 entity in total)
• Functional Keywords: ion channel, mechanosensitive, lipid scramblase, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 92244.90

Authors

Zheng, W.,Fu, T.M.,Holt, J.R. (deposition date: 2025-02-10, release date: 2025-06-11, Last modification date: 2025-08-20)

Primary citation

Zheng, W.,Lowry, A.J.,Smith, H.E.,Xie, J.,Rawson, S.,Wang, C.,Ou, J.,Sotomayor, M.,Fu, T.M.,Yang, H.,Holt, J.R.
Structural and functional basis of mechanosensitive TMEM63 channelopathies.
Neuron, 113:2474-, 2025

PubMed 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.

PubMed: 40480214
DOI: 10.1016/j.neuron.2025.05.009

Experimental method

ELECTRON MICROSCOPY (3.65 Å)