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- EMDB-45934: Structure of human full-length ancestral TRPV6 channel in Calmodu... -

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Basic information

Entry
Database: EMDB / ID: EMD-45934
TitleStructure of human full-length ancestral TRPV6 channel in Calmodulin-bound state
Map data
Sample
  • Complex: ancestral 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
Keywordstransient receptor potential V family member 6 / TRP / channel / TRPV6 / TRP channels / membrane protein / ancestral / 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 / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / TRP channels / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / calcium ion import across plasma membrane / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / Long-term potentiation / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / catalytic complex / Smooth Muscle Contraction / 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 / cellular response to interferon-beta / calcium ion homeostasis / Protein methylation / calcium channel inhibitor activity / Activation of AMPK downstream of NMDARs / presynaptic cytosol / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / sperm midpiece / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / calcium channel complex / FCERI mediated Ca+2 mobilization / substantia nigra development / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / FCGR3A-mediated IL10 synthesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calyx of Held / adenylate cyclase activator activity / sarcomere / VEGFR2 mediated cell proliferation / protein serine/threonine kinase activator activity / VEGFR2 mediated vascular permeability / regulation of cytokinesis / spindle microtubule / calcium channel regulator activity / positive regulation of receptor signaling pathway via JAK-STAT / Translocation of SLC2A4 (GLUT4) to the plasma membrane / RAF activation / Transcriptional activation of mitochondrial biogenesis / response to calcium ion / calcium ion transmembrane transport / cellular response to type II interferon / calcium channel activity / Stimuli-sensing channels / G2/M transition of mitotic cell cycle / long-term synaptic potentiation / spindle pole / RAS processing / Signaling by RAF1 mutants / calcium-dependent protein binding / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / calcium ion transport / 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: 3.42 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-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45934.png

Downloads & links

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Map

FileDownload / File: emd_45934.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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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.152 Å		1.07 Å/pix.
x 256 pix.
= 273.152 Å		1.07 Å/pix.
x 256 pix.
= 273.152 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.067 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.326
Minimum - Maximum-2.180107 - 3.3508096
Average (Standard dev.)0.0045338813 (±0.10287473)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.152 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_45934_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_45934_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : ancestral hTRPV6 tetramer in complex with Calmodulin

EntireName: ancestral hTRPV6 tetramer in complex with Calmodulin
Components
  • Complex: ancestral 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

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Supramolecule #1: ancestral hTRPV6 tetramer in complex with Calmodulin

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

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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: 87.375391 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 GTAFRRSPRN 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 AYVTPKDDIR 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 T 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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMris(hydroxymethyl)aminomethane
1.0 mMbeta-mercaptoethanol
GridModel: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 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: 14833688
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 232058
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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