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- EMDB-22290: Structure of a mitochondrial calcium uniporter holocomplex (MICU1... -

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Basic information

Entry
Database: EMDB / ID: EMD-22290
TitleStructure of a mitochondrial calcium uniporter holocomplex (MICU1, MICU2, MCU, EMRE) in low Ca2+
Map datamain map. Sharpened
Sample
  • Complex: Mitochondrial Calcium Uniporter holocomplex
    • Complex: EMRE
      • Protein or peptide: Protein EMRE homolog, mitochondrial-like Protein
    • Complex: MCU
      • Protein or peptide: Calcium uniporter protein
    • Complex: MICU1-MICU2 heterodimer
      • Protein or peptide: Calcium uptake protein 1, mitochondrial
      • Protein or peptide: Calcium uptake protein 2, mitochondrial
  • Ligand: CALCIUM IONCalcium
Keywordsion channel / calcium channel / mitochondrial calcium uniporter / MCU / EMRE / mitochondria / TRANSPORT PROTEIN-CALCIUM BINDING PROTEIN complex
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 / calcium channel complex / mitochondrial membrane / calcium channel activity / protein homooligomerization / defense response / mitochondrial intermembrane space / mitochondrial inner membrane / protein heterodimerization activity / calcium ion binding / mitochondrion / 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 uniporter protein / Essential MCU regulator, mitochondrial / Calcium uptake protein 2, mitochondrial / Calcium uptake protein 1, mitochondrial
Similarity search - Component
Biological speciesTribolium castaneum (red flour beetle) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLong SB / Wang C
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM131921 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA008748 United States
CitationJournal: Elife / Year: 2020
Title: Structures reveal gatekeeping of the mitochondrial Ca uniporter by MICU1-MICU2.
Authors: Chongyuan Wang / Agata Jacewicz / Bryce D Delgado / Rozbeh Baradaran / Stephen Barstow Long /
Abstract: The mitochondrial calcium uniporter is a Ca-gated ion channel complex that controls mitochondrial Ca entry and regulates cell metabolism. MCU and EMRE form the channel while Ca-dependent regulation ...The mitochondrial calcium uniporter is a Ca-gated ion channel complex that controls mitochondrial Ca entry and regulates cell metabolism. MCU and EMRE form the channel while Ca-dependent regulation is conferred by MICU1 and MICU2 through an enigmatic process. We present a cryo-EM structure of an MCU-EMRE-MICU1-MICU2 holocomplex comprising MCU and EMRE subunits from the beetle Tribolium castaneum in complex with a human MICU1-MICU2 heterodimer at 3.3 Å resolution. With analogy to how neuronal channels are blocked by protein toxins, a uniporter interaction domain on MICU1 binds to a channel receptor site comprising MCU and EMRE subunits to inhibit ion flow under resting Ca conditions. A Ca-bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca-dependent changes enable dynamic response to cytosolic Ca signals.
History
DepositionJul 9, 2020-
Header (metadata) releaseJul 29, 2020-
Map releaseJul 29, 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: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.015
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  • Surface view with fitted model
  • Atomic models: PDB-6xqn
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6xqn
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22290.png

Downloads & links

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Map

FileDownload / File: emd_22290.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map. Sharpened
Voxel sizeX=Y=Z: 1.064 Å
Density
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.09686384 - 0.15410823
Average (Standard dev.)-0.000018437446 (±0.0024044442)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 319.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0641.0641.064
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z319.200319.200319.200
α/β/γ90.00090.00090.000
start NX/NY/NZ434333
NX/NY/NZ116118137
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0970.154-0.000

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Supplemental data

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Additional map: sharpened map calculated from the first 6 frames.

Fileemd_22290_additional_1.map
Annotationsharpened map calculated from the first 6 frames.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: unsharpened map

Fileemd_22290_additional_2.map
Annotationunsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Mitochondrial Calcium Uniporter holocomplex

EntireName: Mitochondrial Calcium Uniporter holocomplex
Components
  • Complex: Mitochondrial Calcium Uniporter holocomplex
    • Complex: EMRE
      • Protein or peptide: Protein EMRE homolog, mitochondrial-like Protein
    • Complex: MCU
      • Protein or peptide: Calcium uniporter protein
    • Complex: MICU1-MICU2 heterodimer
      • Protein or peptide: Calcium uptake protein 1, mitochondrial
      • Protein or peptide: Calcium uptake protein 2, mitochondrial
  • Ligand: CALCIUM IONCalcium

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Supramolecule #1: Mitochondrial Calcium Uniporter holocomplex

SupramoleculeName: Mitochondrial Calcium Uniporter holocomplex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: EMRE

SupramoleculeName: EMRE / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Tribolium castaneum (red flour beetle)

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Supramolecule #3: MCU

SupramoleculeName: MCU / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Tribolium castaneum (red flour beetle)

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Supramolecule #4: MICU1-MICU2 heterodimer

SupramoleculeName: MICU1-MICU2 heterodimer / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein EMRE homolog, mitochondrial-like Protein

MacromoleculeName: Protein EMRE homolog, mitochondrial-like Protein / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Tribolium castaneum (red flour beetle)
Molecular weightTheoretical: 7.37219 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GPTAAALETA VYSKSGGLLP EPHRTSFGII RLILTVVPGL LIGAAISKNI ANFLEENDLF VPSDDDDDDD

UniProtKB: Essential MCU regulator, mitochondrial

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Macromolecule #2: Calcium uniporter protein

MacromoleculeName: Calcium uniporter protein / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Tribolium castaneum (red flour beetle)
Molecular weightTheoretical: 23.6341 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPTAAALERL TTEEVQGLSD VKTLVNQLYE ALNVREHQLQ KEVELTTQLE TLQQELLPLE EKKLELEQVA NRRSNWMAWA GLGLMSVQF GILARLTWWE YSWDIMEPVT YFVTYGTAMA AYAYFVLTRE EYILNDVRDR QQLLLLHKKA KKTGFDVNQY N VLKDQIAK ...String:
GPTAAALERL TTEEVQGLSD VKTLVNQLYE ALNVREHQLQ KEVELTTQLE TLQQELLPLE EKKLELEQVA NRRSNWMAWA GLGLMSVQF GILARLTWWE YSWDIMEPVT YFVTYGTAMA AYAYFVLTRE EYILNDVRDR QQLLLLHKKA KKTGFDVNQY N VLKDQIAK LELDLKRLRD PLKLRLPPKA AAKEEGGWSH PQFEK

UniProtKB: Calcium uniporter protein

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Macromolecule #3: Calcium uptake protein 1, mitochondrial

MacromoleculeName: Calcium uptake protein 1, mitochondrial / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.422883 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPTAAALEPH PEEKKKKRSG FRDRKVMEYE NRIRAYSTPD KIFRYFATLK VISEPGEAEV FMTPEDFVRS ITPNEKQPEH LGLDQYIIK RFDGKKISQE REKFADEGSI FYTLGECGLI SFSDYIFLTT VLSTPQRNFE IAFKMFDLNG DGEVDMEEFE Q VQSIIRSQ ...String:
GPTAAALEPH PEEKKKKRSG FRDRKVMEYE NRIRAYSTPD KIFRYFATLK VISEPGEAEV FMTPEDFVRS ITPNEKQPEH LGLDQYIIK RFDGKKISQE REKFADEGSI FYTLGECGLI SFSDYIFLTT VLSTPQRNFE IAFKMFDLNG DGEVDMEEFE Q VQSIIRSQ TSMGMRHRDR PTTGNTLKSG LCSALTTYFF GADLKGKLTI KNFLEFQRKL QHDVLKLEFE RHDPVDGRIT ER QFGGMLL AYSGVQSKKL TAMQRQLKKH FKEGKGLTFQ EVENFFTFLK NINDVDTALS FYHMAGASLD KVTMQQVART VAK VELSDH VCDVVFALFD CDGNGELSNK EFVSIMKQRL MRGLEKPKDM GFTRLMQAMW KCAQETAWDF ALPKQSNW

UniProtKB: Calcium uptake protein 1, mitochondrial

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Macromolecule #4: Calcium uptake protein 2, mitochondrial

MacromoleculeName: Calcium uptake protein 2, mitochondrial / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.980609 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HHSRVSVAAR DGSFTVSAQK NVEHGIIYIG KPSLRKQRFM QFSSLEHEGE YYMTPRDFLF SVMFEQMERK TSVKKLTKKD IEDTLSGIQ TAGCGSTFFR DLGDKGLISY TEYLFLLTIL TKPHSGFHVA FKMLDTDGNE MIEKREFFKL QKIISKQDDL M TVKTNETG ...String:
HHSRVSVAAR DGSFTVSAQK NVEHGIIYIG KPSLRKQRFM QFSSLEHEGE YYMTPRDFLF SVMFEQMERK TSVKKLTKKD IEDTLSGIQ TAGCGSTFFR DLGDKGLISY TEYLFLLTIL TKPHSGFHVA FKMLDTDGNE MIEKREFFKL QKIISKQDDL M TVKTNETG YQEAIVKEPE INTTLQMRFF GKRGQRKLHY KEFRRFMENL QTEIQEMEFL QFSKGLSFMR KEDFAEWLLF FT NTENKDI YWKNVREKLS AGESISLDEF KSFCHFTTHL EDFAIAMQMF SLAHRPVRLA EFKRAVKVAT GQELSNNILD TVF KIFDLD GDECLSHEEF LGVLKNRMHR GLWVPQHQSI QEYWKCVKKE SIKGVKEVWK QAGKGLF

UniProtKB: Calcium uptake protein 2, mitochondrial

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 1 / 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

Concentration1.0 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMsodium chlorideNaClSodium chloride
5.0 mMEGTA
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV / Details: 2 second blot, blot force of 0.
DetailsMonodisperse sample

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: -3.0 µm / Nominal defocus min: -1.0 µm / Nominal magnification: 22500
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Number grids imaged: 5 / Number real images: 21115 / Average exposure time: 4.0 sec. / Average electron dose: 71.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 17440131
Startup modelType of model: INSILICO MODEL
In silico model: Ab initio model created using CryoSPARC v2.12
Initial angle assignmentType: RANDOM ASSIGNMENT
Software: (Name: cryoSPARC (ver. v2.12.4), RELION (ver. 3.0))
Final 3D classificationNumber classes: 1 / Avg.num./class: 350160 / Software - Name: cryoSPARC (ver. v2.12.4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 350160

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 124 / Target criteria: Correlation coefficient
Output model

PDB-6xqn:
Structure of a mitochondrial calcium uniporter holocomplex (MICU1, MICU2, MCU, EMRE) in low Ca2+

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