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- EMDB-49160: Human TMEM63A mutant V53M closed state -

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Basic information

Entry
Database: EMDB / ID: EMD-49160
TitleHuman TMEM63A mutant V53M closed state
Map dataHuman TMEM63A mutant V53M closed state
Sample
  • Complex: TMEM63A V53M mutant
    • Protein or peptide: CSC1-like protein 1
KeywordsIon channel / Mechanosensitive / lipid scramblase / TRANSPORT PROTEIN
Function / homology
Function and homology information


surfactant secretion / osmolarity-sensing monoatomic cation channel activity / mechanosensitive monoatomic ion channel activity / calcium-activated cation channel activity / tertiary granule membrane / specific granule membrane / centriolar satellite / early endosome membrane / nucleic acid binding / lysosomal membrane ...surfactant secretion / osmolarity-sensing monoatomic cation channel activity / mechanosensitive monoatomic ion channel activity / calcium-activated cation channel activity / 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
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.65 Å
AuthorsZheng W / Fu TM / Holt JR
Funding support United States, 1 items
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, 2025-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49160.png

Downloads & links

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Map

FileDownload / File: emd_49160.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman TMEM63A mutant V53M closed state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 350 pix.
= 255.5 Å		0.73 Å/pix.
x 350 pix.
= 255.5 Å		0.73 Å/pix.
x 350 pix.
= 255.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.019
Minimum - Maximum-0.09147063 - 0.14157104
Average (Standard dev.)0.000086427484 (±0.0021227577)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 255.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_49160_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_49160_half_map_2.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : TMEM63A V53M mutant

EntireName: TMEM63A V53M mutant
Components
  • Complex: TMEM63A V53M mutant
    • Protein or peptide: CSC1-like protein 1

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Supramolecule #1: TMEM63A V53M mutant

SupramoleculeName: TMEM63A V53M mutant / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: CSC1-like protein 1

MacromoleculeName: CSC1-like protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 92.244898 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MMDSPFLELW QSKAVSIREQ LGLGDRPNDS YCYNSAKNST VLQGVTFGGI PTMLLIDVSC FLFLILVFSI IRRRFWDYGR IALVSEADS ESRFQRLSST SSSGQQDFEN ELGCCPWLTA IFRLHDDQIL EWCGEDAIHY LSFQRHIIFL LVVVSFLSLC V ILPVNLSG ...String:
MMDSPFLELW QSKAVSIREQ LGLGDRPNDS YCYNSAKNST VLQGVTFGGI PTMLLIDVSC FLFLILVFSI IRRRFWDYGR IALVSEADS ESRFQRLSST SSSGQQDFEN ELGCCPWLTA IFRLHDDQIL EWCGEDAIHY LSFQRHIIFL LVVVSFLSLC V ILPVNLSG DLLDKDPYSF GRTTIANLQT DNDLLWLHTI FAVIYLFLTV GFMRHHTQSI KYKEENLVRR TLFITGLPRD AR KETVESH FRDAYPTCEV VDVQLCYNVA KLIYLCKEKK KTEKSLTYYT NLQVKTGQRT LINPKPCGQF CCCEVLGCEW EDA ISYYTR MKDRLLERIT EEERHVQDQP LGMAFVTFQE KSMATYILKD FNACKCQSLQ CKGEPQPSSH SRELYTSKWT VTFA ADPED ICWKNLSIQG LRWWLQWLGI NFTLFLGLFF LTTPSIILST MDKFNVTKPI HALNNPIISQ FFPTLLLWSF SALLP SIVY YSTLLESHWT KSGENQIMMT KVYIFLIFMV LILPSLGLTS LDFFFRWLFD KTSSEASIRL ECVFLPDQGA FFVNYV IAS AFIGNGMELL RLPGLILYTF RMIMAKTAAD RRNVKQNQAF QYEFGAMYAW MLCVFTVIVA YSITCPIIAP FGLIYIL LK HMVDRHNLYF VYLPAKLEKG IHFAAVNQAL AAPILCLFWL YFFSFLRLGM KAPATLFTFL VLLLTILVCL AHTCFGCF K HLSPLNYKTE EPASDKGSEA EAHMPPPFTP YVPRILNGLA SERTALSPQQ QQQQTYGAIH NISGTIPGQC LAQSATGSV AAAPQEA

UniProtKB: CSC1-like protein 1

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2 mg/mL
BufferpH: 7.6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 49.32 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 82622
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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