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- PDB-9wxv: Cryo-EM structure of TMEM63A-digitonin-cholesterol -

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Basic information

Entry
Database: PDB / ID: 9wxv
TitleCryo-EM structure of TMEM63A-digitonin-cholesterol
ComponentsMechanosensitive cation channel TMEM63A
KeywordsMEMBRANE PROTEIN / ion channels / lipid scramblase
Function / homology
Function and homology information


surfactant secretion / osmolarity-sensing monoatomic cation channel activity / mechanosensitive monoatomic ion channel activity / calcium-activated cation channel activity / lysosome organization / tertiary granule membrane / specific granule membrane / centriolar satellite / early endosome membrane / nucleic acid binding ...surfactant secretion / osmolarity-sensing monoatomic cation channel activity / mechanosensitive monoatomic ion channel activity / calcium-activated cation channel activity / lysosome organization / tertiary granule membrane / specific granule membrane / centriolar satellite / early endosome membrane / nucleic acid binding / intracellular membrane-bounded organelle / lysosomal membrane / Neutrophil degranulation / extracellular exosome / plasma membrane
Similarity search - Function
CSC1/OSCA1-like, 7TM region / CSC1/OSCA1-like, cytosolic domain / CSC1/OSCA1-like, N-terminal transmembrane domain / Calcium permeable stress-gated cation channel 1-like / Calcium-dependent channel, 7TM region, putative phosphate / Late exocytosis, associated with Golgi transport / Cytosolic domain of 10TM putative phosphate transporter / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily
Similarity search - Domain/homology
CHOLESTEROL / Mechanosensitive cation channel TMEM63A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsLin, Y. / Zhou, Z. / Han, Y. / Cheng, D. / Wang, H. / Ju, L. / Zhang, Y. / Cox, D.C. / Corry, B.
Funding support Australia, China, 3items
OrganizationGrant numberCountry
Australian Research Council (ARC)DP200100860 Australia
Australian Research Council (ARC)FT220100159 Australia
Chinese Academy of Sciences2022ZD0207400 China
CitationJournal: Nat Commun / Year: 2026
Title: TMEM63 proteins act as mechanically activated cholesterol modulated lipid scramblases contributing to membrane mechano-resilience.
Authors: Yiechang Lin / Zijing Zhou / Yaoyao Han / Delfine Cheng / Haoqing Wang / Lining Arnold Ju / Yixiao Zhang / Charles D Cox / Ben Corry /
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 ...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 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.
History
DepositionSep 26, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 11, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Mechanosensitive cation channel TMEM63A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,5173
Polymers92,7431
Non-polymers7732
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Mechanosensitive cation channel TMEM63A / Transmembrane protein 63A / hTMEM63A


Mass: 92743.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM63A, KIAA0489, KIAA0792 / Production host: Homo sapiens (human) / References: UniProt: O94886
#2: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TMEM63A with cholesterol / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.9
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 63.9 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1Gautomatchparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 202829 / Symmetry type: POINT
RefinementHighest resolution: 4.4 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035294
ELECTRON MICROSCOPYf_angle_d0.9887200
ELECTRON MICROSCOPYf_dihedral_angle_d20.539805
ELECTRON MICROSCOPYf_chiral_restr0.118830
ELECTRON MICROSCOPYf_plane_restr0.006866

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