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- EMDB-70008: TMEM16F in liposomes in the absence of Ca2+ (contracted state) -

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Basic information

Entry
Database: EMDB / ID: EMD-70008
TitleTMEM16F in liposomes in the absence of Ca2+ (contracted state)
Map dataPrimary map used for model building
Sample
  • Complex: Dimeric lipid scramblase and ion channel mTMEM16F
    • Protein or peptide: Anoctamin-6
  • Ligand: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate
Keywordsmembrane protein / lipid scramblase / TMEM16 / liposome / LIPID TRANSPORT
Function / homology
Function and homology information


calcium activated galactosylceramide scrambling / phosphatidylserine exposure on blood platelet / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / calcium activated phospholipid scrambling / positive regulation of potassium ion export across plasma membrane / positive regulation of monoatomic ion transmembrane transport / activation of blood coagulation via clotting cascade / purinergic nucleotide receptor signaling pathway / phospholipid scramblase activity ...calcium activated galactosylceramide scrambling / phosphatidylserine exposure on blood platelet / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / calcium activated phospholipid scrambling / positive regulation of potassium ion export across plasma membrane / positive regulation of monoatomic ion transmembrane transport / activation of blood coagulation via clotting cascade / purinergic nucleotide receptor signaling pathway / phospholipid scramblase activity / bone mineralization involved in bone maturation / cholinergic synapse / intracellularly calcium-gated chloride channel activity / pore complex assembly / negative regulation of cell volume / plasma membrane phospholipid scrambling / voltage-gated monoatomic ion channel activity / bleb assembly / positive regulation of phagocytosis, engulfment / Stimuli-sensing channels / voltage-gated chloride channel activity / calcium-activated cation channel activity / positive regulation of monocyte chemotaxis / dendritic cell chemotaxis / chloride transport / phospholipid translocation / chloride channel activity / regulation of postsynaptic membrane potential / positive regulation of endothelial cell apoptotic process / positive regulation of bone mineralization / chloride channel complex / Neutrophil degranulation / chloride transmembrane transport / sodium ion transmembrane transport / synaptic membrane / calcium ion transmembrane transport / blood coagulation / positive regulation of apoptotic process / protein homodimerization activity / metal ion binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Anoctamin, dimerisation domain / Anoctamin, dimerisation domain / Anoctamin / : / Calcium-activated chloride channel
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.49 Å
AuthorsFeng Z / Accardi A
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM152012 United States
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Calcium dependent activation of the TMEM16F scramblase and ion channel.
Authors: Zhang Feng / Omar E Alvarenga / Eleonora Di Zanni / Sangyun Lee / George Khelashvili / Alessio Accardi /
Abstract: The ubiquitous transmembrane protein 16F (TMEM16F) Ca-activated channel and scramblase catalyzes phosphatidylserine externalization to enable blood coagulation, membrane fusion and brain immune ...The ubiquitous transmembrane protein 16F (TMEM16F) Ca-activated channel and scramblase catalyzes phosphatidylserine externalization to enable blood coagulation, membrane fusion and brain immune surveillance. Despite its importance, the molecular mechanisms underlying TMEM16F activation remain poorly understood. Here, we obtained high-resolution cryo-electron microscopy structures of TMEM16F active in liposomes. In high-activity conditions, TMEM16F adopts two conformations, the canonical Ca-bound closed state and one where the upward rotation of the cytosolic domain leads to an X-shaped groove that forms a transmembrane pore and locally thins the membrane. Using mutagenesis, functional assays and molecular dynamics simulations, we show that the X-shaped groove is active and mediates nonselective ion flux and lipid scrambling through distinct pathways; ions move within the protein-delimited pore, whereas lipids skirt the X-shaped groove. Our findings provide a complete picture of TMEM16F Ca-dependent gating and demonstrate that imaging membrane proteins in a native-like environment can allow capturing otherwise inaccessible active states.
History
DepositionApr 3, 2025-
Header (metadata) releaseApr 15, 2026-
Map releaseApr 15, 2026-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70008.png

Downloads & links

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Map

FileDownload / File: emd_70008.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary map used for model building
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 211.2 Å		0.83 Å/pix.
x 256 pix.
= 211.2 Å		0.83 Å/pix.
x 256 pix.
= 211.2 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.11
Minimum - Maximum-0.7290281 - 1.1735611
Average (Standard dev.)0.003065004 (±0.040737107)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 211.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_70008_msk_1.map
Projections & Slices
AxesZYX

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Histogram

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Additional map: Unsharpened map, used to assist model building

Fileemd_70008_additional_1.map
AnnotationUnsharpened map, used to assist model building
Projections & Slices
AxesZYX

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Histogram

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Half map: Halfmap A

Fileemd_70008_half_map_1.map
AnnotationHalfmap A
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: Halfmap B

Fileemd_70008_half_map_2.map
AnnotationHalfmap B
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Sample components

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Entire : Dimeric lipid scramblase and ion channel mTMEM16F

EntireName: Dimeric lipid scramblase and ion channel mTMEM16F
Components
  • Complex: Dimeric lipid scramblase and ion channel mTMEM16F
    • Protein or peptide: Anoctamin-6
  • Ligand: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate

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Supramolecule #1: Dimeric lipid scramblase and ion channel mTMEM16F

SupramoleculeName: Dimeric lipid scramblase and ion channel mTMEM16F / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 210 KDa

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Macromolecule #1: Anoctamin-6

MacromoleculeName: Anoctamin-6 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 106.367727 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQMMTRKVLL NMELEEDDDE DGDIVLENFD QTIVCPTFGS LENQQDFRTP EFEEFNGKPD SLFFTDGQRR IDFILVYEDE SKKENNKKG TNEKQKRKRQ AYESNLICHG LQLEATRSVS DDKLVFVKVH APWEVLCTYA EIMHIKLPLK PNDLKTRSPF G NLNWFTKV ...String:
MQMMTRKVLL NMELEEDDDE DGDIVLENFD QTIVCPTFGS LENQQDFRTP EFEEFNGKPD SLFFTDGQRR IDFILVYEDE SKKENNKKG TNEKQKRKRQ AYESNLICHG LQLEATRSVS DDKLVFVKVH APWEVLCTYA EIMHIKLPLK PNDLKTRSPF G NLNWFTKV LRVNESVIKP EQEFFTAPFE KSRMNDFYIL DRDSFFNPAT RSRIVYFILS RVKYQVMNNV NKFGINRLVS SG IYKAAFP LHDCRFNYES EDISCPSERY LLYREWAHPR SIYKKQPLDL IRKYYGEKIG IYFAWLGYYT QMLLLAAVVG VAC FLYGYL DQDNCTWSKE VCDPDIGGQI LMCPQCDRLC PFWRLNITCE SSKKLCIFDS FGTLIFAVFM GVWVTLFLEF WKRR QAELE YEWDTVELQQ EEQARPEYEA QCNHVVINEI TQEEERIPFT TCGKCIRVTL CASAVFFWIL LIIASVIGII VYRLS VFIV FSTTLPKNPN GTDPIQKYLT PQMATSITAS IISFIIIMIL NTIYEKVAIM ITNFELPRTQ TDYENSLTMK MFLFQF VNY YSSCFYIAFF KGKFVGYPGD PVYLLGKYRS EECDPGGCLL ELTTQLTIIM GGKAIWNNIQ EVLLPWVMNL IGRYKRV SG SEKITPRWEQ DYHLQPMGKL GLFYEYLEMI IQFGFVTLFV ASFPLAPLLA LVNNILEIRV DAWKLTTQFR RMVPEKAQ D IGAWQPIMQG IAILAVVTNA MIIAFTSDMI PRLVYYWSFS IPPYGDHTYY TMDGYINNTL SVFNITDFKN TDKENPYIG LGNYTLCRYR DFRNPPGHPQ EYKHNIYYWH VIAAKLAFII VMEHIIYSVK FFISYAIPDV SKITKSKIKR EKYLTQKLLH ESHLKDLTK NMGIIAERIG GTVDNSVRPK LE

UniProtKB: Anoctamin-6

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Macromolecule #2: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]o...

MacromoleculeName: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate
type: ligand / ID: 2 / Number of copies: 12 / Formula: PGW
Molecular weightTheoretical: 749.007 Da

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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

BufferpH: 7.4
Component:
ConcentrationNameFormula
10.0 mMTris
150.0 mMpotassium chlorideKCl
5.0 mMEGTAC10H16N2O8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 15 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 47.08 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4552656
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.49 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 357583
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6qpb


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: AB INITIO MODEL
Output model

PDB-9o1i:
TMEM16F in liposomes in the absence of Ca2+ (contracted state)

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