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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 FAM155A
KeywordsMEMBRANE PROTEIN / ion channel / channelosome / NALCN
Function / homology
Function and homology information


monoatomic cation homeostasis / positive regulation of synaptic transmission, cholinergic / leak channel activity / viral tegument / regulation of resting membrane potential / cation channel complex / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events ...monoatomic cation homeostasis / positive regulation of synaptic transmission, cholinergic / leak channel activity / viral tegument / regulation of resting membrane potential / cation channel complex / 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 / voltage-gated sodium channel activity / CREB1 phosphorylation through the activation of Adenylate Cyclase / 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 / sodium channel activity / 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 / Calcineurin activates NFAT / protein phosphatase activator activity / Regulation of MECP2 expression and activity / regulation of ryanodine-sensitive calcium-release channel activity / DARPP-32 events / monoatomic ion channel complex / 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 / monoatomic cation channel activity / Protein methylation / 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 / potassium ion transmembrane transport / sperm midpiece / substantia nigra development / calcium channel complex / sodium ion transmembrane transport / 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 / bioluminescence / protein serine/threonine kinase activator activity / VEGFR2 mediated cell proliferation / sarcomere / regulation of cytokinesis / VEGFR2 mediated vascular permeability / positive regulation of synaptic transmission, GABAergic / generation of precursor metabolites and energy / 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 / 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
Similarity search - Function
UNC79 / Cation channel complex component UNC80, N-terminal / Protein UNC80, central region / Protein UNC80, C-terminal / Cation-channel complex subunit UNC-79 / UNC80 N-terminal / Protein UNC80 central region / Protein UNC80 C-terminal region / Sodium leak channel NALCN / : ...UNC79 / Cation channel complex component UNC80, N-terminal / Protein UNC80, central region / Protein UNC80, C-terminal / Cation-channel complex subunit UNC-79 / UNC80 N-terminal / Protein UNC80 central region / Protein UNC80 C-terminal 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
Revision 1.1Jun 26, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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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
Water00
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


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 FIELD / 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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