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- PDB-6wdo: Cryo-EM structure of mitochondrial calcium uniporter holocomplex ... -

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Basic information

Entry
Database: PDB / ID: 6wdo
TitleCryo-EM structure of mitochondrial calcium uniporter holocomplex in high Ca2+
Components
  • (Calcium uniporter protein, ...) x 2
  • (Calcium uptake protein ...) x 2
  • Essential MCU regulator, mitochondrial
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of mitochondrial calcium ion concentration / regulation of cellular hyperosmotic salinity response / uniporter activity / Processing of SMDT1 / mitochondrial calcium ion transmembrane transport / uniplex complex / calcium import into the mitochondrion / Mitochondrial calcium ion transport / positive regulation of mitochondrial calcium ion concentration / mitochondrial calcium ion homeostasis ...negative regulation of mitochondrial calcium ion concentration / regulation of cellular hyperosmotic salinity response / uniporter activity / Processing of SMDT1 / mitochondrial calcium ion transmembrane transport / uniplex complex / calcium import into the mitochondrion / Mitochondrial calcium ion transport / positive regulation of mitochondrial calcium ion concentration / mitochondrial calcium ion homeostasis / calcium ion import / positive regulation of neutrophil chemotaxis / positive regulation of mitochondrial fission / calcium channel complex / calcium-mediated signaling / mitochondrial membrane / calcium channel activity / protein homooligomerization / defense response / mitochondrial intermembrane space / positive regulation of insulin secretion / glucose homeostasis / protein complex oligomerization / mitochondrial inner membrane / mitochondrial matrix / protein heterodimerization activity / calcium ion binding / mitochondrion / nucleoplasm / identical protein binding
Similarity search - Function
Essential MCU regulator, mitochondrial / Putative mitochondrial precursor protein / Calcium uptake protein 1/2/3 / Calcium uniporter protein, C-terminal / MCU family / Mitochondrial calcium uniporter / EF hand / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site ...Essential MCU regulator, mitochondrial / Putative mitochondrial precursor protein / Calcium uptake protein 1/2/3 / Calcium uniporter protein, C-terminal / MCU family / Mitochondrial calcium uniporter / EF hand / 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 / EF-hand domain pair
Similarity search - Domain/homology
Calcium uptake protein 2, mitochondrial / Calcium uniporter protein, mitochondrial / Calcium uptake protein 1, mitochondrial / Essential MCU regulator, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsFeng, L. / Zhang, J. / Fan, M.
CitationJournal: Nature / Year: 2020
Title: Structure and mechanism of the mitochondrial Ca uniporter holocomplex.
Authors: Minrui Fan / Jinru Zhang / Chen-Wei Tsai / Benjamin J Orlando / Madison Rodriguez / Yan Xu / Maofu Liao / Ming-Feng Tsai / Liang Feng /
Abstract: Mitochondria take up Ca through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca signalling and cell death. In mammals, the uniporter complex (uniplex) contains ...Mitochondria take up Ca through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca signalling and cell death. In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for Ca transport. To prevent detrimental Ca overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca concentrations to switch MCU on and off. Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca-activated states. These structures define the architecture of this multicomponent Ca-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca overload.
History
DepositionApr 1, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

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  • EMDB-21643
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Structure viewerMolecule:
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Assembly

Deposited unit
G: Calcium uniporter protein, mitochondrial
H: Essential MCU regulator, mitochondrial
C: Calcium uniporter protein, mitochondrial
D: Essential MCU regulator, mitochondrial
A: Calcium uniporter protein, mitochondrial
B: Essential MCU regulator, mitochondrial
E: Calcium uniporter protein, mitochondrial
F: Essential MCU regulator, mitochondrial
I: Calcium uniporter protein, mitochondrial
J: Essential MCU regulator, mitochondrial
K: Calcium uniporter protein, mitochondrial
L: Essential MCU regulator, mitochondrial
O: Calcium uniporter protein, mitochondrial
P: Essential MCU regulator, mitochondrial
M: Calcium uniporter protein, mitochondrial
N: Essential MCU regulator, mitochondrial
Q: Calcium uptake protein 1, mitochondrial
R: Calcium uptake protein 2, mitochondrial
S: Calcium uptake protein 1, mitochondrial
T: Calcium uptake protein 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)453,37622
Polymers453,29520
Non-polymers802
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area77190 Å2
ΔGint-565 kcal/mol
Surface area180040 Å2

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Components

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Calcium uniporter protein, ... , 2 types, 8 molecules GAEIOMCK

#1: Protein
Calcium uniporter protein, mitochondrial / HsMCU / Coiled-coil domain-containing protein 109A


Mass: 32014.904 Da / Num. of mol.: 6 / Fragment: residues 25-297
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCU, C10orf42, CCDC109A / Production host: Homo sapiens (human) / References: UniProt: Q8NE86
#3: Protein Calcium uniporter protein, mitochondrial / HsMCU / Coiled-coil domain-containing protein 109A


Mass: 31406.152 Da / Num. of mol.: 2 / Fragment: residues 74-341
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCU, C10orf42, CCDC109A / Production host: Homo sapiens (human) / References: UniProt: Q8NE86

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Calcium uptake protein ... , 2 types, 4 molecules QSRT

#4: Protein Calcium uptake protein 1, mitochondrial / Atopy-related autoantigen CALC / ara CALC / Calcium-binding atopy-related autoantigen 1


Mass: 39058.488 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MICU1, CALC, CBARA1 / Production host: Homo sapiens (human) / References: UniProt: Q9BPX6
#5: Protein Calcium uptake protein 2, mitochondrial / EF-hand domain-containing family member A1


Mass: 36682.039 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MICU2, EFHA1 / Production host: Homo sapiens (human) / References: UniProt: Q8IYU8

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Protein / Non-polymers , 2 types, 10 molecules HDBFJLPN

#2: Protein
Essential MCU regulator, mitochondrial / Single-pass membrane protein with aspartate-rich tail 1 / mitochondrial


Mass: 5864.078 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMDT1, C22orf32, EMRE / Production host: Homo sapiens (human) / References: UniProt: Q9H4I9
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca

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Details

Has ligand of interestN

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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: Calcium uniporter protein, mitochondrial, Essential MCU regulator, mitochondrial, Calcium uptake protein 1, mitochondrial, Calcium uptake protein 2, mitochondrial complex
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 7.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R2/1
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 30 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM softwareName: SerialEM / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 128221 / Symmetry type: POINT

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