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- EMDB-8961: Cryo-EM structure of human TRPV6 in complex with Calmodulin -

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Basic information

Entry
Database: EMDB / ID: EMD-8961
TitleCryo-EM structure of human TRPV6 in complex with Calmodulin
Map dataprimary map
Sample
  • Complex: TRPV6-Calmodulin
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
    • Protein or peptide: Calmodulin-1
  • Ligand: CALCIUM ION
KeywordsTRPV6 / TRP channels / Calcium channels / MEMBRANE PROTEIN
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: 3.9 Å
AuthorsSingh AK / McGoldrick LL
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)1R01CA206573-01A1 United States
CitationJournal: Sci Adv / Year: 2018
Title: Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6.
Authors: Appu K Singh / Luke L McGoldrick / Edward C Twomey / Alexander I Sobolevsky /
Abstract: Calcium (Ca) plays a major role in numerous physiological processes. Ca homeostasis is tightly controlled by ion channels, the aberrant regulation of which results in various diseases including ...Calcium (Ca) plays a major role in numerous physiological processes. Ca homeostasis is tightly controlled by ion channels, the aberrant regulation of which results in various diseases including cancers. Calmodulin (CaM)-mediated Ca-induced inactivation is an ion channel regulatory mechanism that protects cells against the toxic effects of Ca overload. We used cryo-electron microscopy to capture the epithelial calcium channel TRPV6 (transient receptor potential vanilloid subfamily member 6) inactivated by CaM. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM carboxyl-terminal lobe plugs the channel through a unique cation-π interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the pore's intracellular entrance. We propose a mechanism of CaM-mediated Ca-induced inactivation that can be explored for therapeutic design.
History
DepositionJul 11, 2018-
Header (metadata) releaseJul 18, 2018-
Map releaseAug 22, 2018-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.38
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.38
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6e2f
  • Surface level: 0.38
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8961.png

Downloads & links

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Map

FileDownload / File: emd_8961.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationprimary map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 250 pix.
= 270. Å		1.08 Å/pix.
x 250 pix.
= 270. Å		1.08 Å/pix.
x 250 pix.
= 270. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.34 / Movie #1: 0.38
Minimum - Maximum-0.66367066 - 1.3814886
Average (Standard dev.)0.01350529 (±0.07352111)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions250250250
Spacing250250250
CellA=B=C: 270.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z250250250
origin x/y/z0.0000.0000.000
length x/y/z270.000270.000270.000
α/β/γ90.00090.00090.000
start NX/NY/NZ-34-26-36
NX/NY/NZ528549
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS250250250
D min/max/mean-0.6641.3810.014

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Supplemental data

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Sample components

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Entire : TRPV6-Calmodulin

EntireName: TRPV6-Calmodulin
Components
  • Complex: TRPV6-Calmodulin
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
    • Protein or peptide: Calmodulin-1
  • Ligand: CALCIUM ION

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Supramolecule #1: TRPV6-Calmodulin

SupramoleculeName: TRPV6-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: 83.302828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPLL LAAKDNDVQA LNKLLKYEDC KVHQRGAMGE TALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT ALHIAVVNQN MNLVRALLAR RASVSARATG TAFRRSPCNL I YFGEHPLS ...String:
MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPLL LAAKDNDVQA LNKLLKYEDC KVHQRGAMGE TALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT ALHIAVVNQN MNLVRALLAR RASVSARATG TAFRRSPCNL I YFGEHPLS FAACVNSEEI VRLLIEHGAD IRAQDSLGNT VLHILILQPN KTFACQMYNL LLSYDRHGDH LQPLDLVPNH QG LTPFKLA GVEGNTVMFQ HLMQKRKHTQ WTYGPLTSTL YDLTEIDSSG DEQSLLELII TTKKREARQI LDQTPVKELV SLK WKRYGR PYFCMLGAIY LLYIICFTMC CIYRPLKPRT NNRTSPRDNT LLQQKLLQEA YMTPKDDIRL VGELVTVIGA IIIL LVEVP DIFRMGVTRF FGQTILGGPF HVLIITYAFM VLVTMVMRLI SASGEVVPMS FALVLGWCNV MYFARGFQML GPFTI MIQK MIFGDLMRFC WLMAVVILGF ASAFYIIFQT EDPEELGHFY DYPMALFSTF ELFLTIIDGP ANYNVDLPFM YSITYA AFA IIATLLMLNL LIAMMGDTHW RVAHERDELW RAQIVATTVM LERKLPRCLW PRSGICGREY GLGDRWFLRV EDRQDLN RQ RIQRYAQAFH TRGSEDLDKD SVEKLELGCP FSPHLSLPMP SVSRSTSRSS ANWERLRQGT LRRDLRGIIN RGLEDGES W 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: Escherichia coli K-12 (bacteria)
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: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / 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

Concentration0.6 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMTRISTRIS
GridSupport film - Material: CARBON / Support film - topology: HOLEY / Details: unidentified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 429167
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

7120

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 180600
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-6e2f:
Cryo-EM structure of human TRPV6 in complex with Calmodulin

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