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- PDB-8wg3: mouse TMEM63b in LMNG-CHS micelle -

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Basic information

Entry
Database: PDB / ID: 8wg3
Titlemouse TMEM63b in LMNG-CHS micelle
ComponentsCSC1-like protein 2,Green fluorescent protein
KeywordsLIPID TRANSPORT / Scramblase
Function / homology
Function and homology information


alveolar lamellar body membrane / sphingomyelin transfer activity / surfactant secretion / phosphatidylcholine transfer activity / mechanosensitive monoatomic cation channel activity / osmolarity-sensing monoatomic cation channel activity / phospholipid scramblase activity / intestinal stem cell homeostasis / drinking behavior / mechanosensitive monoatomic ion channel activity ...alveolar lamellar body membrane / sphingomyelin transfer activity / surfactant secretion / phosphatidylcholine transfer activity / mechanosensitive monoatomic cation channel activity / osmolarity-sensing monoatomic cation channel activity / phospholipid scramblase activity / intestinal stem cell homeostasis / drinking behavior / mechanosensitive monoatomic ion channel activity / calcium-activated cation channel activity / exocytosis / bioluminescence / generation of precursor metabolites and energy / sensory perception of sound / actin cytoskeleton / early endosome membrane / lysosomal membrane / endoplasmic reticulum membrane / 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 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein
Similarity search - Domain/homology
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / CHOLESTEROL HEMISUCCINATE / Green fluorescent protein / Mechanosensitive cation channel TMEM63B
Similarity search - Component
Biological speciesMus musculus (house mouse)
Aequorea victoria (jellyfish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsMiyata, Y. / Takahashi, K. / Lee, Y. / Sultan, C.S. / Kuribayashi, R. / Takahashi, M. / Hata, K. / Bamba, T. / Izumi, Y. / Liu, K. ...Miyata, Y. / Takahashi, K. / Lee, Y. / Sultan, C.S. / Kuribayashi, R. / Takahashi, M. / Hata, K. / Bamba, T. / Izumi, Y. / Liu, K. / Uemura, T. / Nomura, N. / Iwata, S. / Nagata, S. / Nishizawa, T. / Segawa, K.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution.
Authors: Yugo Miyata / Katsuya Takahashi / Yongchan Lee / Cheryl S Sultan / Risa Kuribayashi / Masatomo Takahashi / Kosuke Hata / Takeshi Bamba / Yoshihiro Izumi / Kehong Liu / Tomoko Uemura / ...Authors: Yugo Miyata / Katsuya Takahashi / Yongchan Lee / Cheryl S Sultan / Risa Kuribayashi / Masatomo Takahashi / Kosuke Hata / Takeshi Bamba / Yoshihiro Izumi / Kehong Liu / Tomoko Uemura / Norimichi Nomura / So Iwata / Shigekazu Nagata / Tomohiro Nishizawa / Katsumori Segawa /
Abstract: Phospholipids are asymmetrically distributed in the plasma membrane (PM), with phosphatidylcholine and sphingomyelin abundant in the outer leaflet. However, the mechanisms by which their distribution ...Phospholipids are asymmetrically distributed in the plasma membrane (PM), with phosphatidylcholine and sphingomyelin abundant in the outer leaflet. However, the mechanisms by which their distribution is regulated remain unclear. Here, we show that transmembrane protein 63B (TMEM63B) functions as a membrane structure-responsive lipid scramblase localized at the PM and lysosomes, activating bidirectional lipid translocation upon changes in membrane curvature and thickness. TMEM63B contains two intracellular loops with palmitoylated cysteine residue clusters essential for its scrambling function. TMEM63B deficiency alters phosphatidylcholine and sphingomyelin distributions in the PM. Persons with heterozygous mutations in TMEM63B are known to develop neurodevelopmental disorders. We show that V44M, the most frequent substitution, confers constitutive scramblase activity on TMEM63B, disrupting PM phospholipid asymmetry. We determined the cryo-electron microscopy structures of TMEM63B in its open and closed conformations, uncovering a lipid translocation pathway formed in response to changes in the membrane environment. Together, our results identify TMEM63B as a membrane structure-responsive scramblase that controls PM lipid distribution and we reveal the molecular basis for lipid scrambling and its biological importance.
History
DepositionSep 20, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.0Sep 25, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.1Oct 22, 2025Group: Data collection / Database references / Structure summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CSC1-like protein 2,Green fluorescent protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,9805
Polymers126,7591
Non-polymers2,2204
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 CSC1-like protein 2,Green fluorescent protein


Mass: 126759.461 Da / Num. of mol.: 1 / Mutation: F64L,S65T,A206K,H231L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse), (gene. exp.) Aequorea victoria (jellyfish)
Gene: Tmem63b, GFP / Cell line (production host): FreeStyle 293-F / Production host: Homo sapiens (human) / References: UniProt: Q3TWI9, UniProt: P42212
#2: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C31H50O4
#3: Chemical ChemComp-LBN / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / (2R)-2-[(9Z)-9-Octadecenoyloxy]-3-(palmitoyloxy)propyl 2-(trimethylammonio)ethyl phosphate


Mass: 760.076 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: mouse TMEM63B / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.1 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Mus musculus (house mouse)10090
31Aequorea victoria (jellyfish)6100
Source (recombinant)Organism: Homo sapiens (human) / Cell: FreeStyle 293-F
Buffer solutionpH: 8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 279 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.2.1particle selection
2EPUimage acquisition
4cryoSPARC4.2.1CTF correction
7Coot0.9.9.8model fitting
8ISOLDE1.4.3model fitting
10cryoSPARC4.2.1initial Euler assignment
11cryoSPARC4.2.1final Euler assignment
12cryoSPARC4.2.1classification
13cryoSPARC4.2.13D reconstruction
14Servalcat0.2.24model refinement
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 110878 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model buildingAccession code: Q3TWI9 / Source name: AlphaFold / Type: in silico model
RefinementResolution: 3.4→3.4 Å / Cor.coef. Fo:Fc: 0.811 / SU B: 19.951 / SU ML: 0.324 / ESU R: 0.276
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.44152 --
obs0.44152 138849 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 148.666 Å2
Refinement stepCycle: 1 / Total: 4586
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0060.0124724
ELECTRON MICROSCOPYr_bond_other_d00.0164582
ELECTRON MICROSCOPYr_angle_refined_deg1.531.6466430
ELECTRON MICROSCOPYr_angle_other_deg0.5121.56410518
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.8345542
ELECTRON MICROSCOPYr_dihedral_angle_2_deg18.132531
ELECTRON MICROSCOPYr_dihedral_angle_3_deg16.07410739
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0820.2738
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.025259
ELECTRON MICROSCOPYr_gen_planes_other0.0010.021141
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it1714.5292186
ELECTRON MICROSCOPYr_mcbond_other16.99614.5312187
ELECTRON MICROSCOPYr_mcangle_it27.54426.0872722
ELECTRON MICROSCOPYr_mcangle_other27.54326.0892723
ELECTRON MICROSCOPYr_scbond_it15.66315.5122538
ELECTRON MICROSCOPYr_scbond_other15.66115.5132539
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other25.95928.0173709
ELECTRON MICROSCOPYr_long_range_B_refined43.445162.9318297
ELECTRON MICROSCOPYr_long_range_B_other43.444162.9318298
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.2→3.283 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.647 10207 -
obs--100 %

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