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- PDB-9n95: Human TMEM63A mutant V53M closed state -

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Basic information

Entry
Database: PDB / ID: 9n95
TitleHuman TMEM63A mutant V53M closed state
ComponentsCSC1-like protein 1
KeywordsTRANSPORT PROTEIN / Ion channel / Mechanosensitive / 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 / lysosomal membrane / intracellular membrane-bounded organelle / 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
Mechanosensitive cation channel TMEM63A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.65 Å
AuthorsZheng, W. / Fu, T.M. / Holt, J.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD)DC01352 United States
CitationJournal: Neuron / Year: 2025
Title: Structural and functional basis of mechanosensitive TMEM63 channelopathies.
Authors: Wang Zheng / Augustus J Lowry / Harper E Smith / Jiale Xie / Shaun Rawson / Chen Wang / Jin Ou / Marcos Sotomayor / Tian-Min Fu / Huanghe Yang / Jeffrey R Holt /
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 ...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.
History
DepositionFeb 10, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jun 11, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2Aug 20, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CSC1-like protein 1


Theoretical massNumber of molelcules
Total (without water)92,2451
Polymers92,2451
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein CSC1-like protein 1 / Transmembrane protein 63A


Mass: 92244.898 Da / Num. of mol.: 1 / Mutation: V53M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM63A, KIAA0489, KIAA0792 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: O94886
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 V53M mutant / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.6
SpecimenConc.: 2 mg/ml / Embedding 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: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 49.32 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 82622 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034801
ELECTRON MICROSCOPYf_angle_d0.6646535
ELECTRON MICROSCOPYf_dihedral_angle_d7.797645
ELECTRON MICROSCOPYf_chiral_restr0.04759
ELECTRON MICROSCOPYf_plane_restr0.004795

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