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- EMDB-15919: Structure of mTMEM16F in lipid Nanodiscs in the presence of Ca2+ -

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Basic information

Entry
Database: EMDB / ID: EMD-15919
TitleStructure of mTMEM16F in lipid Nanodiscs in the presence of Ca2+
Map data
Sample
  • Complex: mTMEM16F Homodimer bound to Ca2+
    • Protein or peptide: Anoctamin-6
  • Ligand: CALCIUM ION
Function / homology
Function and homology information


calcium activated phospholipid scrambling / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / calcium activated galactosylceramide scrambling / positive regulation of potassium ion export across plasma membrane / purinergic nucleotide receptor signaling pathway / positive regulation of monoatomic ion transmembrane transport / phospholipid scramblase activity / intracellularly calcium-gated chloride channel activity / bone mineralization involved in bone maturation ...calcium activated phospholipid scrambling / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / calcium activated galactosylceramide scrambling / positive regulation of potassium ion export across plasma membrane / purinergic nucleotide receptor signaling pathway / positive regulation of monoatomic ion transmembrane transport / phospholipid scramblase activity / intracellularly calcium-gated chloride channel activity / bone mineralization involved in bone maturation / negative regulation of cell volume / cholinergic synapse / voltage-gated monoatomic ion channel activity / plasma membrane phospholipid scrambling / positive regulation of phagocytosis, engulfment / bleb assembly / Stimuli-sensing channels / calcium-activated cation channel activity / positive regulation of monocyte chemotaxis / dendritic cell chemotaxis / chloride transport / phospholipid translocation / chloride channel activity / chloride channel complex / regulation of postsynaptic membrane potential / positive regulation of bone mineralization / chloride transmembrane transport / Neutrophil degranulation / establishment of localization in cell / synaptic membrane / calcium ion transmembrane transport / blood coagulation / positive regulation of apoptotic process / protein homodimerization activity / identical protein binding / metal ion binding / plasma membrane
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: 2.94 Å
AuthorsArndt M / Alvadia C / Straub MS / Clerico-Mosina V / Paulino C / Dutzler R
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)339116European Union
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis for the activation of the lipid scramblase TMEM16F.
Authors: Melanie Arndt / Carolina Alvadia / Monique S Straub / Vanessa Clerico Mosina / Cristina Paulino / Raimund Dutzler /
Abstract: TMEM16F, a member of the conserved TMEM16 family, plays a central role in the initiation of blood coagulation and the fusion of trophoblasts. The protein mediates passive ion and lipid transport in ...TMEM16F, a member of the conserved TMEM16 family, plays a central role in the initiation of blood coagulation and the fusion of trophoblasts. The protein mediates passive ion and lipid transport in response to an increase in intracellular Ca. However, the mechanism of how the protein facilitates both processes has remained elusive. Here we investigate the basis for TMEM16F activation. In a screen of residues lining the proposed site of conduction, we identify mutants with strongly activating phenotype. Structures of these mutants determined herein by cryo-electron microscopy show major rearrangements leading to the exposure of hydrophilic patches to the membrane, whose distortion facilitates lipid diffusion. The concomitant opening of a pore promotes ion conduction in the same protein conformation. Our work has revealed a mechanism that is distinct for this branch of the family and that will aid the development of a specific pharmacology for a promising drug target.
History
DepositionOct 4, 2022-
Header (metadata) releaseDec 21, 2022-
Map releaseDec 21, 2022-
UpdateDec 21, 2022-
Current statusDec 21, 2022Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15919.png

Downloads & links

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Map

FileDownload / File: emd_15919.map.gz / Format: CCP4 / Size: 536.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 520 pix.
= 338.52 Å		0.65 Å/pix.
x 520 pix.
= 338.52 Å		0.65 Å/pix.
x 520 pix.
= 338.52 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.651 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0692
Minimum - Maximum-0.201101 - 0.38626805
Average (Standard dev.)-0.00027872727 (±0.0061522005)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions520520520
Spacing520520520
CellA=B=C: 338.52002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_15919_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_15919_half_map_2.map
Projections & Slices
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Sample components

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Entire : mTMEM16F Homodimer bound to Ca2+

EntireName: mTMEM16F Homodimer bound to Ca2+
Components
  • Complex: mTMEM16F Homodimer bound to Ca2+
    • Protein or peptide: Anoctamin-6
  • Ligand: CALCIUM ION

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Supramolecule #1: mTMEM16F Homodimer bound to Ca2+

SupramoleculeName: mTMEM16F Homodimer bound to Ca2+ / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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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: 113.454602 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 IISHIIIMIL 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 LEALEVLFQG PQGTEQKLIS EEDLRGASMD EKTTGWRGGH VVEGLAGELE Q LRARLEHH PQGQREP

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Macromolecule #2: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 6 / Formula: CA
Molecular weightTheoretical: 40.078 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: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 66.6 e/Å2
Details: 3 Datasets were collected from differenct grids. Eposure time was between 66.6 e-/A2 for GO grids, 84.2 e-/A2 for UltrAu foil grids, and 76 e-/A2 for UltrAu foil grids with 20deg tilt collection
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 282719
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6qp6

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 85
Output model

PDB-8b8q:
Structure of mTMEM16F in lipid Nanodiscs in the presence of Ca2+

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