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- PDB-7xqb: Structure of connexin43/Cx43/GJA1 gap junction intercellular chan... -

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Basic information

Entry
Database: PDB / ID: 7xqb
TitleStructure of connexin43/Cx43/GJA1 gap junction intercellular channel in POPE/CHS nanodiscs at pH ~8.0
ComponentsGap junction alpha-1 protein
KeywordsMEMBRANE PROTEIN / Cx43 / Connexin / Gap junction channel / Gating mechanism
Function / homology
Function and homology information


gap junction channel activity involved in cardiac conduction electrical coupling / negative regulation of gonadotropin secretion / positive regulation of striated muscle tissue development / milk ejection reflex / positive regulation of morphogenesis of an epithelium / positive regulation of mesodermal cell differentiation / atrial ventricular junction remodeling / cell communication by chemical coupling / cell communication by electrical coupling / neuroblast migration ...gap junction channel activity involved in cardiac conduction electrical coupling / negative regulation of gonadotropin secretion / positive regulation of striated muscle tissue development / milk ejection reflex / positive regulation of morphogenesis of an epithelium / positive regulation of mesodermal cell differentiation / atrial ventricular junction remodeling / cell communication by chemical coupling / cell communication by electrical coupling / neuroblast migration / columnar/cuboidal epithelial cell maturation / negative regulation of trophoblast cell migration / microtubule-based transport / gap junction hemi-channel activity / monoatomic ion transmembrane transporter activity / regulation of bone remodeling / SARS-CoV-2 targets PDZ proteins in cell-cell junction / gap junction channel activity involved in cell communication by electrical coupling / regulation of ventricular cardiac muscle cell membrane depolarization / contractile muscle fiber / Oligomerization of connexins into connexons / Transport of connexins along the secretory pathway / glutathione transmembrane transporter activity / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / gap junction assembly / atrial cardiac muscle cell action potential / Regulation of gap junction activity / cardiac conduction system development / regulation of atrial cardiac muscle cell membrane depolarization / cellular response to pH / connexin complex / fascia adherens / gap junction / cell-cell contact zone / Formation of annular gap junctions / Golgi-associated vesicle membrane / cell communication by electrical coupling involved in cardiac conduction / Gap junction degradation / bone remodeling / skeletal muscle tissue regeneration / gap junction channel activity / Gap junction assembly / regulation of bone mineralization / export across plasma membrane / adult heart development / regulation of ventricular cardiac muscle cell membrane repolarization / tight junction / glutamate secretion / blood vessel morphogenesis / lens development in camera-type eye / intermediate filament / xenobiotic transport / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / embryonic digit morphogenesis / maintenance of blood-brain barrier / positive regulation of stem cell proliferation / beta-tubulin binding / RHOJ GTPase cycle / RHOQ GTPase cycle / heart looping / establishment of mitotic spindle orientation / efflux transmembrane transporter activity / intercalated disc / alpha-tubulin binding / lateral plasma membrane / T cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / tubulin binding / protein tyrosine kinase binding / negative regulation of cell growth / beta-catenin binding / bone development / cellular response to amyloid-beta / male gonad development / neuron migration / osteoblast differentiation / cell junction / intracellular protein localization / cell-cell signaling / positive regulation of cold-induced thermogenesis / heart development / scaffold protein binding / monoatomic ion transmembrane transport / spermatogenesis / in utero embryonic development / positive regulation of canonical NF-kappaB signal transduction / apical plasma membrane / membrane raft / Golgi membrane / signaling receptor binding / negative regulation of gene expression / focal adhesion / intracellular membrane-bounded organelle / positive regulation of gene expression / endoplasmic reticulum membrane / Golgi apparatus / signal transduction / mitochondrion / nucleoplasm / nucleus
Similarity search - Function
Gap junction channel protein cysteine-rich domain / Gap junction alpha-1 protein (Cx43) / Gap junction alpha-1 protein (Cx43), C-terminal / Gap junction alpha-1 protein (Cx43), alpha helix domain superfamily / Gap junction alpha-1 protein (Cx43) / Connexin, C-terminal / Connexin / Connexin, N-terminal / Connexin, conserved site / Gap junction protein, cysteine-rich domain ...Gap junction channel protein cysteine-rich domain / Gap junction alpha-1 protein (Cx43) / Gap junction alpha-1 protein (Cx43), C-terminal / Gap junction alpha-1 protein (Cx43), alpha helix domain superfamily / Gap junction alpha-1 protein (Cx43) / Connexin, C-terminal / Connexin / Connexin, N-terminal / Connexin, conserved site / Gap junction protein, cysteine-rich domain / Connexin, N-terminal domain superfamily / Connexin / Connexins signature 1. / Connexins signature 2. / Connexin homologues / Gap junction channel protein cysteine-rich domain / de novo design (two linked rop proteins) / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
TETRADECANE / PHOSPHATIDYLETHANOLAMINE / CHOLESTEROL HEMISUCCINATE / Gap junction alpha-1 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsLee, H.J. / Cha, H.J. / Jeong, H. / Lee, S.N. / Lee, C.W. / Woo, J.S.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2018R1C1B6004447 Korea, Republic Of
CitationJournal: Nat Commun / Year: 2023
Title: Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM.
Authors: Hyuk-Joon Lee / Hyung Jin Cha / Hyeongseop Jeong / Seu-Na Lee / Chang-Won Lee / Minsoo Kim / Jejoong Yoo / Jae-Sung Woo /
Abstract: Connexin family proteins assemble into hexameric hemichannels in the cell membrane. The hemichannels dock together between two adjacent membranes to form gap junction intercellular channels (GJIChs). ...Connexin family proteins assemble into hexameric hemichannels in the cell membrane. The hemichannels dock together between two adjacent membranes to form gap junction intercellular channels (GJIChs). We report the cryo-electron microscopy structures of Cx43 GJICh, revealing the dynamic equilibrium state of various channel conformations in detergents and lipid nanodiscs. We identify three different N-terminal helix conformations of Cx43-gate-covering (GCN), pore-lining (PLN), and flexible intermediate (FIN)-that are randomly distributed in purified GJICh particles. The conformational equilibrium shifts to GCN by cholesteryl hemisuccinates and to PLN by C-terminal truncations and at varying pH. While GJIChs that mainly comprise GCN protomers are occluded by lipids, those containing conformationally heterogeneous protomers show markedly different pore sizes. We observe an α-to-π-helix transition in the first transmembrane helix, which creates a side opening to the membrane in the FIN and PLN conformations. This study provides basic structural information to understand the mechanisms of action and regulation of Cx43 GJICh.
History
DepositionMay 7, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Gap junction alpha-1 protein
G: Gap junction alpha-1 protein
B: Gap junction alpha-1 protein
C: Gap junction alpha-1 protein
D: Gap junction alpha-1 protein
E: Gap junction alpha-1 protein
F: Gap junction alpha-1 protein
H: Gap junction alpha-1 protein
I: Gap junction alpha-1 protein
J: Gap junction alpha-1 protein
K: Gap junction alpha-1 protein
L: Gap junction alpha-1 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)563,413180
Polymers516,73612
Non-polymers46,677168
Water00
1


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

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Components

#1: Protein
Gap junction alpha-1 protein / Connexin-43 / Cx43 / Gap junction 43 kDa heart protein


Mass: 43061.336 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GJA1, GJAL / Production host: Homo sapiens (human) / References: UniProt: P17302
#2: Chemical...
ChemComp-C14 / TETRADECANE


Mass: 198.388 Da / Num. of mol.: 132 / Source method: obtained synthetically / Formula: C14H30
#3: Chemical...
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: C31H50O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-PTY / PHOSPHATIDYLETHANOLAMINE


Mass: 734.039 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C40H80NO8P / Comment: phospholipid*YM
Has ligand of interestY
Has protein modificationY

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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: Dodecameric complex of human Cx43/GJA1 in lipid nanodiscs (POPE/CHS)
Type: COMPLEX
Details: Human Cx43 gap junction channel with gate-covering NTH conformation
Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2750 nm / Nominal defocus min: 1250 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21621 / Symmetry type: POINT
RefinementCross valid method: NONE
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.006423256
ELECTRON MICROSCOPYf_angle_d0.613730816
ELECTRON MICROSCOPYf_chiral_restr0.03983312
ELECTRON MICROSCOPYf_plane_restr0.00533396
ELECTRON MICROSCOPYf_dihedral_angle_d15.94379168

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