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- PDB-7wji: Architecture of the human NALCN channelosome -

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Basic information

Entry
Database: PDB / ID: 7wji
TitleArchitecture of the human NALCN channelosome
Components
  • Calmodulin-1
  • Protein unc-79 homolog
  • Protein unc-80 homolog
  • Sodium leak channel non-selective protein,Extended tegument protein pp150
  • Transmembrane protein FAM155ATransmembrane protein
KeywordsMEMBRANE PROTEIN / ion channel / channelosome / NALCN
Function / homology
Function and homology information


monoatomic cation homeostasis / positive regulation of synaptic transmission, cholinergic / leak channel activity / regulation of resting membrane potential / viral tegument / cation channel complex / sodium channel activity / voltage-gated sodium channel activity / CaM pathway / Cam-PDE 1 activation ...monoatomic cation homeostasis / positive regulation of synaptic transmission, cholinergic / leak channel activity / regulation of resting membrane potential / viral tegument / cation channel complex / sodium channel activity / voltage-gated sodium channel activity / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / monoatomic ion channel complex / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / Activation of RAC1 downstream of NMDARs / mitochondrion-endoplasmic reticulum membrane tethering / CLEC7A (Dectin-1) induces NFAT activation / regulation of cardiac muscle cell action potential / autophagosome membrane docking / positive regulation of ryanodine-sensitive calcium-release channel activity / Negative regulation of NMDA receptor-mediated neuronal transmission / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-threonine phosphorylation / Unblocking of NMDA receptors, glutamate binding and activation / Synthesis of IP3 and IP4 in the cytosol / Phase 0 - rapid depolarisation / protein phosphatase activator activity / RHO GTPases activate PAKs / calcium ion import across plasma membrane / positive regulation of cyclic-nucleotide phosphodiesterase activity / positive regulation of phosphoprotein phosphatase activity / Ion transport by P-type ATPases / Long-term potentiation / Uptake and function of anthrax toxins / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / catalytic complex / DARPP-32 events / detection of calcium ion / sodium ion transmembrane transport / negative regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction / calcium channel inhibitor activity / cellular response to interferon-beta / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / voltage-gated potassium channel complex / eNOS activation / Activation of AMPK downstream of NMDARs / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / regulation of calcium-mediated signaling / positive regulation of protein dephosphorylation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / titin binding / monoatomic cation channel activity / Ion homeostasis / regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of protein autophosphorylation / potassium ion transmembrane transport / sperm midpiece / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / protein serine/threonine kinase activator activity / bioluminescence / sarcomere / monoatomic ion transmembrane transport / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / positive regulation of peptidyl-threonine phosphorylation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / regulation of cytokinesis / generation of precursor metabolites and energy / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / positive regulation of synaptic transmission, GABAergic / calcium ion transmembrane transport / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of protein serine/threonine kinase activity / Transcriptional activation of mitochondrial biogenesis / Stimuli-sensing channels / spindle pole / cellular response to type II interferon
Similarity search - Function
Protein UNC80, C-terminal / Cation-channel complex subunit UNC-79 / Protein UNC80 C-terminal region / UNC79 / Cation channel complex component UNC80, N-terminal / Protein UNC80, central region / UNC80 N-terminal / Protein UNC80 central region / Sodium leak channel NALCN / Herpesvirus UL11/UL32 ...Protein UNC80, C-terminal / Cation-channel complex subunit UNC-79 / Protein UNC80 C-terminal region / UNC79 / Cation channel complex component UNC80, N-terminal / Protein UNC80, central region / UNC80 N-terminal / Protein UNC80 central region / Sodium leak channel NALCN / Herpesvirus UL11/UL32 / Herpesvirus large structural phosphoprotein UL32 / Voltage-dependent channel domain superfamily / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / EF-hand domain pair / EF-hand, calcium binding motif / 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 / Armadillo-type fold
Similarity search - Domain/homology
Extended tegument protein pp150 / NALCN channel auxiliary factor 1 / Calmodulin-1 / Sodium leak channel NALCN / Protein unc-80 homolog / Protein unc-79 homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsWu, J.P. / Yan, Z. / Zhou, L. / Liu, H. / Zhao, Q.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Discov / Year: 2022
Title: Architecture of the human NALCN channelosome.
Authors: Lunni Zhou / Haobin Liu / Qingqing Zhao / Jianping Wu / Zhen Yan /
Abstract: NALCN regulates the resting membrane potential by mediating the Na leak current in neurons, and it functions as a channelosome in complex with FAM155A, UNC79, and UNC80. Dysfunction of the NALCN ...NALCN regulates the resting membrane potential by mediating the Na leak current in neurons, and it functions as a channelosome in complex with FAM155A, UNC79, and UNC80. Dysfunction of the NALCN channelosome causes a broad range of neurological and developmental diseases called NALCN channelopathies in humans. How the auxiliary subunits, especially the two large components UNC79 and UNC80, assemble with NALCN and regulate its function remains unclear. Here we report an overall architecture of the human NALCN channelosome. UNC79 and UNC80 each adopt an S-shape super-helical structure consisting of HEAT and armadillo repeats, forming a super-coiled heterodimeric assembly in the cytoplasmic side, which may provide a scaffold for the binding of other potential modulators of the channelosome. The UNC79-UNC80 assembly specifically associates with the NALCN-FAM155A subcomplex through the intracellular II-III linker of NALCN. Disruptions of the interaction interfaces between UNC79 and UNC80, and between the II-III linker of NALCN and the UNC79-UNC80 assembly, significantly reduce the NALCN-mediated currents in HEK293T system, suggesting the importance of the UNC79-UNC80 assembly in regulating channelosome function. Cross-linking mass spectrometry analysis identified an additional calmodulin (CaM) bound in the carboxyl-terminal domain of NALCN. Our study thus provides a structural basis for understanding the unique assembly mechanism and functional regulation of the NALCN channelosome, and also provides an opportunity for the interpretation of many disease-related mutations in UNC80.
History
DepositionJan 6, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein unc-80 homolog
B: Protein unc-79 homolog
E: Calmodulin-1
C: Sodium leak channel non-selective protein,Extended tegument protein pp150
D: Transmembrane protein FAM155A


Theoretical massNumber of molelcules
Total (without water)959,5175
Polymers959,5175
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Protein unc-80 homolog


Mass: 363856.188 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UNC80, C2orf21, KIAA1843 / Production host: Homo sapiens (human) / References: UniProt: Q8N2C7
#2: Protein Protein unc-79 homolog


Mass: 298239.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UNC79, KIAA1409 / Production host: Homo sapiens (human) / References: UniProt: Q9P2D8
#3: Protein Calmodulin-1 /


Mass: 16852.545 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Homo sapiens (human) / References: UniProt: P0DP23
#4: Protein Sodium leak channel non-selective protein,Extended tegument protein pp150 / CanIon / Voltage gated channel-like protein 1


Mass: 229017.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NALCN, VGCNL1, UL32 / Production host: Homo sapiens (human) / References: UniProt: Q8IZF0, UniProt: A0A076JQ90
#5: Protein Transmembrane protein FAM155A / Transmembrane protein


Mass: 51550.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FAM155A / Production host: Homo sapiens (human) / References: UniProt: B1AL88

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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: NALCN channelosome / Type: COMPLEX / Details: NALCN-FAM155A-UNC79-UNC80-CaM / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.9 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 81000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 174294 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00742111
ELECTRON MICROSCOPYf_angle_d1.07357053
ELECTRON MICROSCOPYf_dihedral_angle_d16.7935492
ELECTRON MICROSCOPYf_chiral_restr0.0596520
ELECTRON MICROSCOPYf_plane_restr0.0087172

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