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- EMDB-45936: Structure of human full-length derived TRPV6 channel in Calmoduli... -

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Basic information

Entry
Database: EMDB / ID: EMD-45936
TitleStructure of human full-length derived TRPV6 channel in Calmodulin-bound state
Map data
Sample
  • Complex: derived hTRPV6 tetramer in complex with Calmodulin
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
    • Protein or peptide: Calmodulin-1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CALCIUM ION
  • Ligand: water
Keywordstransient receptor potential V family member 6 / TRP / channel / TRPV6 / TRP channels / membrane protein / derived / calmodulin
Function / homology
Function and homology information


parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 ...parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / TRP channels / PKA activation / CaMK IV-mediated phosphorylation of CREB / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of calcium ion export across plasma membrane / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / presynaptic endocytosis / regulation of cardiac muscle cell action potential / positive regulation of ryanodine-sensitive calcium-release channel activity / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of ryanodine-sensitive calcium-release channel activity / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / calcineurin-mediated signaling / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / calcium ion import across plasma membrane / Long-term potentiation / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / protein phosphatase activator activity / regulation of ryanodine-sensitive calcium-release channel activity / DARPP-32 events / Smooth Muscle Contraction / catalytic complex / detection of calcium ion / regulation of cardiac muscle contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / presynaptic cytosol / calcium channel inhibitor activity / cellular response to interferon-beta / Protein methylation / calcium ion homeostasis / Activation of AMPK downstream of NMDARs / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / regulation of calcium-mediated signaling / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / titin binding / voltage-gated potassium channel complex / sperm midpiece / substantia nigra development / calcium channel complex / calyx of Held / FCERI mediated Ca+2 mobilization / Ras activation upon Ca2+ influx through NMDA receptor / FCGR3A-mediated IL10 synthesis / adenylate cyclase activator activity / regulation of heart rate / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / protein serine/threonine kinase activator activity / VEGFR2 mediated cell proliferation / sarcomere / regulation of cytokinesis / VEGFR2 mediated vascular permeability / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of receptor signaling pathway via JAK-STAT / spindle microtubule / RAF activation / Transcriptional activation of mitochondrial biogenesis / calcium ion transmembrane transport / calcium channel activity / Stimuli-sensing channels / cellular response to type II interferon / long-term synaptic potentiation / response to calcium ion / RAS processing / spindle pole / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / calcium ion transport / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / Signaling by BRAF and RAF1 fusions / Inactivation, recovery and regulation of the phototransduction cascade / Platelet degranulation / myelin sheath
Similarity search - Function
Transient receptor potential cation channel subfamily V member 6 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / : / Ankyrin repeat / EF-hand domain pair / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats ...Transient receptor potential cation channel subfamily V member 6 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / : / Ankyrin repeat / EF-hand domain pair / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / EF-hand, calcium binding motif / Ankyrin repeat-containing domain superfamily / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / EF-hand domain pair
Similarity search - Domain/homology
Calmodulin-1 / Transient receptor potential cation channel subfamily V member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsNeuberger A / Nadezhdin KD / Sobolevsky AI
Funding support United States, Germany, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA206573 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS083660 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS107253 United States
German Research Foundation (DFG)464295817 Germany
CitationJournal: Structure / Year: 2025
Title: Structure-function analyses of human TRPV6 ancestral and derived haplotypes.
Authors: Arthur Neuberger / Alexey Shalygin / Yury A Trofimov / Irina I Veretenenko / Kirill D Nadezhdin / Nikolay A Krylov / Thomas Gudermann / Roman G Efremov / Vladimir Chubanov / Alexander I Sobolevsky /
Abstract: TRPV6 is a Ca selective channel that mediates calcium uptake in the gut and contributes to the development and progression of human cancers. TRPV6 is represented by the ancestral and derived ...TRPV6 is a Ca selective channel that mediates calcium uptake in the gut and contributes to the development and progression of human cancers. TRPV6 is represented by the ancestral and derived haplotypes that differ by three non-synonymous polymorphisms, located in the N-terminal ankyrin repeat domain (C157R), S1-S2 extracellular loop (M378V), and C-terminus (M681T). The ancestral and derived haplotypes were proposed to serve as genomic factors causing a different outcome for cancer patients of African ancestry. We solved cryoelectron microscopy (cryo-EM) structures of ancestral and derived TRPV6 in the open and calmodulin (CaM)-bound inactivated states. Neither state shows substantial structural differences caused by the non-synonymous polymorphisms. Functional properties assessed by electrophysiological recordings and Ca uptake measurements, and water and ion permeation evaluated by molecular modeling also appear similar between the haplotypes. Therefore, ancestral and derived TRPV6 have similar structure and function, implying that other factors are responsible for the differences in susceptibility to cancer.
History
DepositionJul 26, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45936.png

Downloads & links

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Map

FileDownload / File: emd_45936.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.109
Minimum - Maximum-0.67382294 - 0.95553637
Average (Standard dev.)0.0030236156 (±0.042964913)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_45936_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_45936_half_map_2.map
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Sample components

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Entire : derived hTRPV6 tetramer in complex with Calmodulin

EntireName: derived hTRPV6 tetramer in complex with Calmodulin
Components
  • Complex: derived hTRPV6 tetramer in complex with Calmodulin
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
    • Protein or peptide: Calmodulin-1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CALCIUM ION
  • Ligand: water

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Supramolecule #1: derived hTRPV6 tetramer in complex with Calmodulin

SupramoleculeName: derived hTRPV6 tetramer in complex with Calmodulin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 370 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 6

MacromoleculeName: Transient receptor potential cation channel subfamily V member 6
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.3835 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGPLQGDGGP ALGGADVAPR LSPVRVWPRP QAPKEPALHP MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPL LLAAKDNDVQ ALNKLLKYED CKVHQRGAMG ETALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT A LHIAVVNQ ...String:
MGPLQGDGGP ALGGADVAPR LSPVRVWPRP QAPKEPALHP MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPL LLAAKDNDVQ ALNKLLKYED CKVHQRGAMG ETALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT A LHIAVVNQ NMNLVRALLA RRASVSARAT GTAFRRSPCN LIYFGEHPLS FAACVNSEEI VRLLIEHGAD IRAQDSLGNT VL HILILQP NKTFACQMYN LLLSYDRHGD HLQPLDLVPN HQGLTPFKLA GVEGNTVMFQ HLMQKRKHTQ WTYGPLTSTL YDL TEIDSS GDEQSLLELI ITTKKREARQ ILDQTPVKEL VSLKWKRYGR PYFCMLGAIY LLYIICFTMC CIYRPLKPRT NNRT SPRDN TLLQQKLLQE AYMTPKDDIR LVGELVTVIG AIIILLVEVP DIFRMGVTRF FGQTILGGPF HVLIITYAFM VLVTM VMRL ISASGEVVPM SFALVLGWCN VMYFARGFQM LGPFTIMIQK MIFGDLMRFC WLMAVVILGF ASAFYIIFQT EDPEEL GHF YDYPMALFST FELFLTIIDG PANYNVDLPF MYSITYAAFA IIATLLMLNL LIAMMGDTHW RVAHERDELW RAQIVAT TV MLERKLPRCL WPRSGICGRE YGLGDRWFLR VEDRQDLNRQ RIQRYAQAFH TRGSEDLDKD SVEKLELGCP FSPHLSLP M PSVSRSTSRS SANWERLRQG TLRRDLRGII NRGLEDGESW EYQI

UniProtKB: Transient receptor potential cation channel subfamily V member 6

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Macromolecule #2: Calmodulin-1

MacromoleculeName: Calmodulin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.852545 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK

UniProtKB: Calmodulin-1

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 8 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 5 / Number of copies: 43 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 7 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration1.9 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMtris(hydroxymethyl)aminomethane
1.0 mMbeta-Mercaptoethanol
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
Detailshuman TRPV6 in cNW11 nanodiscs

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 11520 pixel / Digitization - Dimensions - Height: 8184 pixel / Number grids imaged: 1 / Number real images: 12516 / Average exposure time: 2.5 sec. / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / 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

Particle selectionNumber selected: 9029804
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 72482
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-9cuk:
Structure of human full-length derived TRPV6 channel in Calmodulin-bound state

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