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- EMDB-21642: Cryo-EM structure of mitochondrial calcium uniporter holocomplex ... -

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Basic information

Entry
Database: EMDB / ID: EMD-21642
TitleCryo-EM structure of mitochondrial calcium uniporter holocomplex in low Ca2+
Map datamembrane protein
Sample
  • Organelle or cellular component: Calcium uptake protein 2, mitochondrial, Calcium uptake protein 1, mitochondrial, Essential MCU regulator, mitochondrial, Calcium uniporter protein, mitochondrial complex
    • Protein or peptide: Calcium uptake protein 2, mitochondrial
    • Protein or peptide: Calcium uptake protein 1, mitochondrial
    • Protein or peptide: Essential MCU regulator, mitochondrial
    • Protein or peptide: Calcium uniporter protein, mitochondrial
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 intermembrane space / mitochondrial membrane / calcium channel activity / 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: 3.2 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-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.38
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.38
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wdn
  • Surface level: 0.38
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21642.png

Downloads & links

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Map

FileDownload / File: emd_21642.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.)
1.06 Å/pix.
x 360 pix.
= 381.6 Å		1.06 Å/pix.
x 360 pix.
= 381.6 Å		1.06 Å/pix.
x 360 pix.
= 381.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.38 / Movie #1: 0.38
Minimum - Maximum-0.7984821 - 2.0070467
Average (Standard dev.)-0.000111656285 (±0.04295358)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 381.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z381.600381.600381.600
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-0.7982.007-0.000

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Supplemental data

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Sample components

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Entire : Calcium uptake protein 2, mitochondrial, Calcium uptake protein 1...

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

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Supramolecule #1: Calcium uptake protein 2, mitochondrial, Calcium uptake protein 1...

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

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Macromolecule #1: Calcium uptake protein 2, mitochondrial

MacromoleculeName: Calcium uptake protein 2, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.755582 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SLRKQRFMQF SSLEHEGEYY MTPRDFLFSV MFEQMERKTS VKKLTKKDIE DTLSGIQTAG CGSTFFRDLG DKGLISYTEY LFLLTILTK PHSGFHVAFK MLDTDGNEMI EKREFFKLQK IISKQDDLMT VKTNETGYQE AIVKEPEINT TLQMRFFGKR G QRKLHYKE ...String:
SLRKQRFMQF SSLEHEGEYY MTPRDFLFSV MFEQMERKTS VKKLTKKDIE DTLSGIQTAG CGSTFFRDLG DKGLISYTEY LFLLTILTK PHSGFHVAFK MLDTDGNEMI EKREFFKLQK IISKQDDLMT VKTNETGYQE AIVKEPEINT TLQMRFFGKR G QRKLHYKE FRRFMENLQT EIQEMEFLQF SKGLSFMRKE DFAEWLLFFT NTENKDIYWK NVREKLSAGE SISLDEFKSF CH FTTHLED FAIAMQMFSL AHRPVRLAEF KRAVKVATGQ ELSNNILDTV FKIFDLDGDE CLSHEEFLGV LKNRMHRGLW VPQ HQSIQE YWKCVKKES

UniProtKB: Calcium uptake protein 2, mitochondrial

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Macromolecule #2: Calcium uptake protein 1, mitochondrial

MacromoleculeName: Calcium uptake protein 1, mitochondrial / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.900891 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 RLMRGLEKPK DMGFTRLMQA MWKCAQE

UniProtKB: Calcium uptake protein 1, mitochondrial

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Macromolecule #3: Essential MCU regulator, mitochondrial

MacromoleculeName: Essential MCU regulator, mitochondrial / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.667833 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VIVTRSGAIL PKPVKMSFGL LRVFSIVIPF LYVGTLISKN FAALLEEHDI F

UniProtKB: Essential MCU regulator, mitochondrial

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Macromolecule #4: Calcium uniporter protein, mitochondrial

MacromoleculeName: Calcium uniporter protein, mitochondrial / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.256521 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SHENAATLND VKTLVQQLYT TLCIEQHQLN KERELIERLE DLKEQLAPLE KVRIEISRKA EKRTTLVLWG GLAYMATQFG ILARLTWWE YSWDIMEPVT YFITYGSAMA MYAYFVMTRQ EYVYPEARDR QYLLFFHKGA KKSRFDLEKY NQLKDAIAQA E MDLKRLRD PLQVHLPLRQ

UniProtKB: Calcium uniporter protein, mitochondrial

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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 TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 53.0 e/Å2
Electron beamAcceleration voltage: 300 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: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 53216
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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