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- EMDB-21643: Cryo-EM structure of mitochondrial calcium uniporter holocomplex ... -

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Basic information

Entry
Database: EMDB / ID: EMD-21643
TitleCryo-EM structure of mitochondrial calcium uniporter holocomplex in high Ca2+
Map datamembrane protein
Sample
  • Organelle or cellular component: Calcium uniporter protein, mitochondrial, Essential MCU regulator, mitochondrial, Calcium uptake protein 1, mitochondrial, Calcium uptake protein 2, mitochondrial complex
    • Protein or peptide: Calcium uniporter protein, mitochondrial
    • Protein or peptide: Essential MCU regulator, mitochondrial
    • Protein or peptide: Calcium uniporter protein, mitochondrial
    • Protein or peptide: Calcium uptake protein 1, mitochondrial
    • Protein or peptide: Calcium uptake protein 2, mitochondrial
  • Ligand: CALCIUM ION
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


mitochondrial crista junction / negative regulation of mitochondrial calcium ion concentration / regulation of cellular hyperosmotic salinity response / positive regulation of cristae formation / uniporter activity / mitochondrial calcium ion transmembrane transport / uniplex complex / Processing of SMDT1 / positive regulation of mitochondrial calcium ion concentration / Mitochondrial calcium ion transport ...mitochondrial crista junction / negative regulation of mitochondrial calcium ion concentration / regulation of cellular hyperosmotic salinity response / positive regulation of cristae formation / uniporter activity / mitochondrial calcium ion transmembrane transport / uniplex complex / Processing of SMDT1 / positive regulation of mitochondrial calcium ion concentration / Mitochondrial calcium ion transport / mitochondrial calcium ion homeostasis / calcium import into the mitochondrion / calcium ion sensor activity / channel activator activity / cellular response to calcium ion starvation / calcium ion import / positive regulation of neutrophil chemotaxis / positive regulation of mitochondrial fission / protein complex oligomerization / calcium channel inhibitor activity / calcium channel complex / Mitochondrial protein degradation / cellular response to calcium ion / calcium channel regulator activity / calcium-mediated signaling / defense response / positive regulation of insulin secretion / protein homooligomerization / mitochondrial membrane / calcium channel activity / mitochondrial intermembrane space / glucose homeostasis / protein-macromolecule adaptor activity / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsFeng L / Zhang J
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, 2020-
Header (metadata) releaseApr 8, 2020-
Map releaseMay 27, 2020-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.32
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.32
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wdo
  • Surface level: 0.32
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21643.png

Downloads & links

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Map

FileDownload / File: emd_21643.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmembrane protein
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 360 pix.
= 396. Å		1.1 Å/pix.
x 360 pix.
= 396. Å		1.1 Å/pix.
x 360 pix.
= 396. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.32 / Movie #1: 0.32
Minimum - Maximum-0.7333747 - 1.5883976
Average (Standard dev.)0.00038442158 (±0.043572683)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 396.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z396.000396.000396.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ280280280
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS360360360
D min/max/mean-0.7331.5880.000

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Supplemental data

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Sample components

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Entire : Calcium uniporter protein, mitochondrial, Essential MCU regulator...

EntireName: Calcium uniporter protein, mitochondrial, Essential MCU regulator, mitochondrial, Calcium uptake protein 1, mitochondrial, Calcium uptake protein 2, mitochondrial complex
Components
  • Organelle or cellular component: Calcium uniporter protein, mitochondrial, Essential MCU regulator, mitochondrial, Calcium uptake protein 1, mitochondrial, Calcium uptake protein 2, mitochondrial complex
    • Protein or peptide: Calcium uniporter protein, mitochondrial
    • Protein or peptide: Essential MCU regulator, mitochondrial
    • Protein or peptide: Calcium uniporter protein, mitochondrial
    • Protein or peptide: Calcium uptake protein 1, mitochondrial
    • Protein or peptide: Calcium uptake protein 2, mitochondrial
  • Ligand: CALCIUM ION

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Supramolecule #1: Calcium uniporter protein, mitochondrial, Essential MCU regulator...

SupramoleculeName: Calcium uniporter protein, mitochondrial, Essential MCU regulator, mitochondrial, Calcium uptake protein 1, mitochondrial, Calcium uptake protein 2, mitochondrial complex
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Calcium uniporter protein, mitochondrial

MacromoleculeName: Calcium uniporter protein, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.014904 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DVTVVYQNGL PVISVRLPSR RERCQFTLKP ISDSVGVFLR QLQEEDRGID RVAIYSPDGV RVAASTGIDL LLLDDFKLVI NDLTYHVRP PKRDLLSHEN AATLNDVKTL VQQLYTTLCI EQHQLNKERE LIERLEDLKE QLAPLEKVRI EISRKAEKRT T LVLWGGLA ...String:
DVTVVYQNGL PVISVRLPSR RERCQFTLKP ISDSVGVFLR QLQEEDRGID RVAIYSPDGV RVAASTGIDL LLLDDFKLVI NDLTYHVRP PKRDLLSHEN AATLNDVKTL VQQLYTTLCI EQHQLNKERE LIERLEDLKE QLAPLEKVRI EISRKAEKRT T LVLWGGLA YMATQFGILA RLTWWEYSWD IMEPVTYFIT YGSAMAMYAY FVMTRQEYVY PEARDRQYLL FFHKGAKKSR FD LEKYNQL KDAIAQAEMD LKRLRDPLQV HLPLRQ

UniProtKB: Calcium uniporter protein, mitochondrial

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Macromolecule #2: Essential MCU regulator, mitochondrial

MacromoleculeName: Essential MCU regulator, mitochondrial / type: protein_or_peptide / ID: 2 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.864078 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VIVTRSGAIL PKPVKMSFGL LRVFSIVIPF LYVGTLISKN FAALLEEHDI FVP

UniProtKB: Essential MCU regulator, mitochondrial

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Macromolecule #3: Calcium uniporter protein, mitochondrial

MacromoleculeName: Calcium uniporter protein, mitochondrial / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 31.406152 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DVTVVYQNGL PVISVRLPSR RERCQFTLKP ISDSVGVFLR QLQEEDRGID RVAIYSPDGV RVAASTGIDL LLLDDFKLVI NDLTYHVRP PKRDLLSHEN AATLNDVKTL VQQLYTTLCI EQHQLNKERE LIERLEDLKE QLAPLEKVRI EISRKAEKRT T LVLWGGLA ...String:
DVTVVYQNGL PVISVRLPSR RERCQFTLKP ISDSVGVFLR QLQEEDRGID RVAIYSPDGV RVAASTGIDL LLLDDFKLVI NDLTYHVRP PKRDLLSHEN AATLNDVKTL VQQLYTTLCI EQHQLNKERE LIERLEDLKE QLAPLEKVRI EISRKAEKRT T LVLWGGLA YMATQFGILA RLTWWEYSWD IMEPVTYFIT YGSAMAMYAY FVMTRQEYVY PEARDRQYLL FFHKGAKKSR FD LEKYNQL KDAIAQAEMD LKRLRDPLQV H

UniProtKB: Calcium uniporter protein, mitochondrial

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Macromolecule #4: Calcium uptake protein 1, mitochondrial

MacromoleculeName: Calcium uptake protein 1, mitochondrial / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.058488 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SGFRDRKVME YENRIRAYST PDKIFRYFAT LKVISEPGEA EVFMTPEDFV RSITPNEKQP EHLGLDQYII KRFDGKKISQ EREKFADEG SIFYTLGECG LISFSDYIFL TTVLSTPQRN FEIAFKMFDL NGDGEVDMEE FEQVQSIIRS QTSMGMRHRD R PTTGNTLK ...String:
SGFRDRKVME YENRIRAYST PDKIFRYFAT LKVISEPGEA EVFMTPEDFV RSITPNEKQP EHLGLDQYII KRFDGKKISQ EREKFADEG SIFYTLGECG LISFSDYIFL TTVLSTPQRN FEIAFKMFDL NGDGEVDMEE FEQVQSIIRS QTSMGMRHRD R PTTGNTLK SGLCSALTTY FFGADLKGKL TIKNFLEFQR KLQHDVLKLE FERHDPVDGR ITERQFGGML LAYSGVQSKK LT AMQRQLK KHFKEGKGLT FQEVENFFTF LKNINDVDTA LSFYHMAGAS LDKVTMQQVA RTVAKVELSD HVCDVVFALF DCD GNGELS NKEFVSIMKQ RLM

UniProtKB: Calcium uptake protein 1, mitochondrial

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Macromolecule #5: Calcium uptake protein 2, mitochondrial

MacromoleculeName: Calcium uptake protein 2, mitochondrial / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.682039 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LRKQRFMQFS SLEHEGEYYM TPRDFLFSVM FEQMERKTSV KKLTKKDIED TLSGIQTAGC GSTFFRDLGD KGLISYTEYL FLLTILTKP HSGFHVAFKM LDTDGNEMIE KREFFKLQKI ISKQDDLMTV KTNETGYQEA IVKEPEINTT LQMRFFGKRG Q RKLHYKEF ...String:
LRKQRFMQFS SLEHEGEYYM TPRDFLFSVM FEQMERKTSV KKLTKKDIED TLSGIQTAGC GSTFFRDLGD KGLISYTEYL FLLTILTKP HSGFHVAFKM LDTDGNEMIE KREFFKLQKI ISKQDDLMTV KTNETGYQEA IVKEPEINTT LQMRFFGKRG Q RKLHYKEF RRFMENLQTE IQEMEFLQFS KGLSFMRKED FAEWLLFFTN TENKDIYWKN VREKLSAGES ISLDEFKSFC HF TTHLEDF AIAMQMFSLA HRPVRLAEFK RAVKVATGQE LSNNILDTVF KIFDLDGDEC LSHEEFLGVL KNR

UniProtKB: Calcium uptake protein 2, mitochondrial

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 2 / 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

Concentration7.9 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R2/1 / Material: GOLD / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 128221
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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