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

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Basic information

Entry
Database: PDB / ID: 8b8q
TitleStructure of mTMEM16F in lipid Nanodiscs in the presence of Ca2+
ComponentsAnoctamin-6
KeywordsMEMBRANE PROTEIN / Lipid Transport / Lipid Scramblase / Ion Channel / Blood Coagulation / Membrane Fusion
Function / homology
Function and homology information


calcium activated phospholipid scrambling / calcium activated galactosylceramide scrambling / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / positive regulation of potassium ion export across plasma membrane / positive regulation of monoatomic ion transmembrane transport / purinergic nucleotide receptor signaling pathway / phospholipid scramblase activity / cholinergic synapse / bone mineralization involved in bone maturation ...calcium activated phospholipid scrambling / calcium activated galactosylceramide scrambling / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / positive regulation of potassium ion export across plasma membrane / positive regulation of monoatomic ion transmembrane transport / purinergic nucleotide receptor signaling pathway / phospholipid scramblase activity / cholinergic synapse / bone mineralization involved in bone maturation / intracellularly calcium-gated chloride channel activity / plasma membrane phospholipid scrambling / negative regulation of cell volume / voltage-gated monoatomic ion channel activity / positive regulation of phagocytosis, engulfment / bleb assembly / Stimuli-sensing channels / calcium-activated cation channel activity / positive regulation of monocyte chemotaxis / chloride transport / dendritic cell chemotaxis / phospholipid translocation / regulation of postsynaptic membrane potential / positive regulation of bone mineralization / chloride channel complex / Neutrophil degranulation / chloride transmembrane transport / synaptic membrane / establishment of localization in cell / calcium ion transmembrane transport / blood coagulation / positive regulation of apoptotic process / protein homodimerization activity / metal ion binding / identical protein 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsArndt, M. / Alvadia, C. / Straub, M.S. / Clerico-Mosina, V. / Paulino, C. / Dutzler, R.
Funding supportEuropean Union, 1items
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, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 21, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Anoctamin-6
B: Anoctamin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,1508
Polymers226,9092
Non-polymers2406
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2120 Å2
ΔGint-89 kcal/mol
Surface area65660 Å2
MethodPISA

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Components

#1: Protein Anoctamin-6 / Small-conductance calcium-activated nonselective cation channel / SCAN channel / Transmembrane protein 16F


Mass: 113454.602 Da / Num. of mol.: 2 / Mutation: F518H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ano6, Tmem16f / Production host: Homo sapiens (human) / References: UniProt: Q6P9J9
#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
Has protein modificationY

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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: mTMEM16F Homodimer bound to Ca2+ / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingElectron dose: 66.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
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

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameCategory
7Cootmodel fitting
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 282719 / Symmetry type: POINT
Atomic model buildingB value: 85 / Protocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6QP6

6qp6


Accession code: 6QP6 / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411674
ELECTRON MICROSCOPYf_angle_d0.5215828
ELECTRON MICROSCOPYf_dihedral_angle_d12.6284222
ELECTRON MICROSCOPYf_chiral_restr0.0391734
ELECTRON MICROSCOPYf_plane_restr0.0041958

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