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Protein

Calcium uniporter protein, mitochondrial

Gene

Mcu

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Mitochondrial inner membrane calcium uniporter that mediates calcium uptake into mitochondria (PubMed:21685886, PubMed:23900286, PubMed:24212091). Constitutes the pore-forming and calcium-conducting subunit of the uniporter complex (uniplex) (By similarity). Activity is regulated by MICU1 and MICU2 (By similarity). At low Ca2+ levels MCU activity is down-regulated by MICU1 and MICU2; at higher Ca2+ levels MICU1 increases MCU activity (By similarity). Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways (By similarity). Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes (By similarity). While dispensable for baseline homeostatic cardiac function, acts as a key regulator of short-term mitochondrial calcium loading underlying a 'fight-or-flight' response during acute stress: acts by mediating a rapid increase of mitochondrial calcium in pacemaker cells (PubMed:26119742, PubMed:26119731, PubMed:25603276). Participates in mitochondrial permeability transition during ischemia-reperfusion injury (PubMed:26119731). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (By similarity). Mitochondrial calcium uptake in skeletal muscle cells is involved in muscle size in adults (PubMed:25732818). Regulates synaptic vesicle endocytosis kinetics in central nerve terminal (PubMed:26644474). Involved in antigen processing and presentation (PubMed:25251370).By similarity9 Publications

Enzyme regulationi

Inhibited by ruthenium red or its derivative Ru360.By similarity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Calcium channel, Ion channel

Keywords - Biological processi

Calcium transport, Ion transport, Transport

Keywords - Ligandi

Calcium

Protein family/group databases

TCDBi1.A.77.1.1. the mg(2+)/ca(2+) uniporter (mcu) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Calcium uniporter protein, mitochondrialCurated
Gene namesi
Name:McuImported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:3026965. Mcu.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini50 – 232Mitochondrial matrixBy similarityAdd BLAST183
Transmembranei233 – 256HelicalSequence analysisAdd BLAST24
Topological domaini257 – 264Mitochondrial intermembraneBy similarity8
Transmembranei265 – 282HelicalSequence analysisAdd BLAST18
Topological domaini283 – 350Mitochondrial matrixBy similarityAdd BLAST68

GO - Cellular componenti

  • calcium channel complex Source: UniProtKB
  • integral component of mitochondrial inner membrane Source: UniProtKB
  • mitochondrial inner membrane Source: UniProtKB
  • mitochondrion Source: MGI
  • uniplex complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Membrane, Mitochondrion, Mitochondrion inner membrane

Pathology & Biotechi

Disruption phenotypei

No visible phenotype (PubMed:24212091, PubMed:26057074). Although slightly smaller, mice are grossly normal. Only minor alterations in basal energetics are observed. Cells show a strong reduction, but not a complete absence, of mitochondrial matrix calcium. The skeletal muscles exhibit alterations in the phosphorylation and activity of pyruvate dehydrogenase and mice show defects in ability to perform strenuous work. Mitochondria lack evidence for calcium-induced permeability transition pore (PTP) opening (PubMed:24212091). Mitochondria from mutant mouse heart muscle have impaired Ca2+ uptake and reduced Ca2+ levels in the mitochondrial matrix; still, mutant mice have apparently normal heart function and display no cardiac defects (PubMed:26057074). Conditional mutant mice with cardiomyocyte-specific deletion of Mcu in adults display no overt baseline phenotype and are protected against mitochondrial calcium overload by preventing the activation of the mitochondrial permeability transition pore (PubMed:26119742, PubMed:26119731). Mice however lack contractile responsiveness to acute stress and 'fight-or-flight' response: they produce mitochondria refractory to acute calcium uptake, with impaired ATP production and inhibited mitochondrial permeability transition pore opening upon acute calcium challenge (PubMed:26119742, PubMed:26119731).4 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi251R → W: Strongly reduces calcium channel activity; when associated with V-256. 1 Publication1
Mutagenesisi256E → V: Strongly reduces calcium channel activity; when associated with W-251. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 49MitochondrionSequence analysisAdd BLAST49
ChainiPRO_000028297750 – 350Calcium uniporter protein, mitochondrialAdd BLAST301

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei56Phosphoserine; by CaMK2By similarity1
Modified residuei91Phosphoserine; by CaMK2By similarity1
Modified residuei331N6-acetyllysineCombined sources1

Post-translational modificationi

Phosphorylation by CaMK2 in heart leads to increased MCU current. The regulation of MCU by CaMK2 is however subject to discussion: another group was unable to reproduce these results. Phosphorylated on tyrosines by PTK2B/PYK2, promoting oligomerization.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ3UMR5.
MaxQBiQ3UMR5.
PaxDbiQ3UMR5.
PeptideAtlasiQ3UMR5.
PRIDEiQ3UMR5.

PTM databases

iPTMnetiQ3UMR5.
PhosphoSitePlusiQ3UMR5.
SwissPalmiQ3UMR5.

Expressioni

Tissue specificityi

Detected in heart muscle (at protein level) (PubMed:26057074). Expressed in skeletal muscle, heart, kidney, liver, brain, lung, white fat and spleen.4 Publications

Gene expression databases

BgeeiENSMUSG00000009647.
CleanExiMM_CCDC109A.
ExpressionAtlasiQ3UMR5. baseline and differential.
GenevisibleiQ3UMR5. MM.

Interactioni

Subunit structurei

Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1 (By similarity). Heterooligomer with CCDC109B/MCUB; this inhibits channel activity (PubMed:23900286). Homooligomer. Homotetramer (PubMed:23900286). Interacts with MICU1; MICU1 acts as an essential regulator for MCU. Interacts with MCUR1. Interactions with MICU1 and MCUR1 are mutually exclusive. Interacts with MICU2 (By similarity). Interacts with SLC25A23 (By similarity).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself2EBI-776370,EBI-776370
Ccdc109bQ810S13EBI-776370,EBI-8847756

Protein-protein interaction databases

IntActiQ3UMR5. 4 interactors.
STRINGi10090.ENSMUSP00000020312.

Structurei

3D structure databases

ProteinModelPortaliQ3UMR5.
SMRiQ3UMR5.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni74 – 164N-terminal MCU domainBy similarityAdd BLAST91
Regioni215 – 233Outer juxtamembrane helix (OJMH)By similarityAdd BLAST19
Regioni282 – 291Inner juxtamembrane helix (IJMH)By similarity10

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili191 – 220Sequence analysisAdd BLAST30
Coiled coili310 – 338Sequence analysisAdd BLAST29

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi260 – 263DXXEBy similarity4

Domaini

The N-terminal domain is required for efficient Ca2+ uptake and for interaction with MCUR1. It is not required for targeting to the mitochondria, oligomerization, interaction with MICU1 and MICU2, or assembly of the uniplex complex.By similarity
Forms a well-packed pentamer with an overall cylindrical shape. The inner core of the pentamer is formed with the second transmembrane region and the second coiled-coil region: while the transmembrane regions pack into a five-helix bundle having a largely polar pore across the membrane, the coiled-coil outside the membrane forms a pentamer with a hydrophobic core. The inner core is wrapped by the first transmembrane region through contacts between the first and the second transmembrane regions. The second transmembrane is followed by the inner juxtamembrane region (IJMH) that orients at a wide angle relative to the second transmembrane. The two core domains are held together on the periphery by the outer juxtamembrane helix (OJMH).By similarity
The critical DXXE motif connecting the transmembrane regions forms a pentameric barrel that constitutes the mouth of the pore. Inside the barrel, two acidic residues are in position to form two carboxylate rings. In absence of SMDT1/EMRE regulator, the calcium ions cannot exit the channel, suggesting that SMDT1/EMRE-binding induces conformational rearrangements to allow calcium to exit.By similarity

Sequence similaritiesi

Keywords - Domaini

Coiled coil, Transit peptide, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2966. Eukaryota.
ENOG410Y3YU. LUCA.
GeneTreeiENSGT00390000004496.
HOVERGENiHBG060246.
InParanoidiQ3UMR5.
OMAiGAVYCST.
OrthoDBiEOG091G092C.
PhylomeDBiQ3UMR5.
TreeFamiTF314435.

Family and domain databases

InterProiIPR006769. Coiled-coil-dom_prot_109_C.
[Graphical view]
PfamiPF04678. MCU. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q3UMR5-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAAAAGRSLL LLLCSRGGGG GAGGCGALTA GCFPGLGVSR HRPHQQHRTA
60 70 80 90 100
HQRPASWQSV GAAYCSTVVP SDDVTVVYQN GLPVISVRLP SRRERCQFTL
110 120 130 140 150
KPISDSVGVF LRQLQEEDRG IDRVAIYSPD GVRVAASTGI DLLLLDDFKL
160 170 180 190 200
VINDLTYHVR PPKRDLLSHE DAATLNDVKT LVQQLYTTLC IEQHQLNKER
210 220 230 240 250
ELVERLEDLK QQLAPLEKVR IEISRKAEKR TTLVLWGGLA YMATQFGILA
260 270 280 290 300
RLTWWEYSWD IMEPVTYFIT YGSAMAMYAY FVMTRQEYVY PEARDRQYLL
310 320 330 340 350
FFHKGAKKSR FDLEKYNQLK DAIAQAEMDL KRLRDPLQVH LPLRQIGEKE
Length:350
Mass (Da):39,682
Last modified:April 3, 2007 - v2
Checksum:iFB3089AADF7FB2E3
GO
Isoform 2 (identifier: Q3UMR5-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-149: Missing.
     150-164: LVINDLTYHVRPPKR → MILRPKQLFSAFTKQ

Show »
Length:201
Mass (Da):23,902
Checksum:i4A2D6D6293C7C586
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0242641 – 149Missing in isoform 2. 2 PublicationsAdd BLAST149
Alternative sequenceiVSP_024265150 – 164LVIND…RPPKR → MILRPKQLFSAFTKQ in isoform 2. 2 PublicationsAdd BLAST15

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK144727 mRNA. Translation: BAE26033.1.
AK161322 mRNA. Translation: BAE36322.1.
AC155940 Genomic DNA. No translation available.
AC022699 Genomic DNA. No translation available.
BC139254 mRNA. Translation: AAI39255.1.
BC139257 mRNA. Translation: AAI39258.1.
CCDSiCCDS23866.2. [Q3UMR5-1]
RefSeqiNP_001028431.2. NM_001033259.4. [Q3UMR5-1]
UniGeneiMm.296470.

Genome annotation databases

EnsembliENSMUST00000009791; ENSMUSP00000009791; ENSMUSG00000009647. [Q3UMR5-2]
ENSMUST00000020312; ENSMUSP00000020312; ENSMUSG00000009647. [Q3UMR5-1]
GeneIDi215999.
KEGGimmu:215999.
UCSCiuc007fds.3. mouse. [Q3UMR5-2]
uc007fdt.3. mouse. [Q3UMR5-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK144727 mRNA. Translation: BAE26033.1.
AK161322 mRNA. Translation: BAE36322.1.
AC155940 Genomic DNA. No translation available.
AC022699 Genomic DNA. No translation available.
BC139254 mRNA. Translation: AAI39255.1.
BC139257 mRNA. Translation: AAI39258.1.
CCDSiCCDS23866.2. [Q3UMR5-1]
RefSeqiNP_001028431.2. NM_001033259.4. [Q3UMR5-1]
UniGeneiMm.296470.

3D structure databases

ProteinModelPortaliQ3UMR5.
SMRiQ3UMR5.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ3UMR5. 4 interactors.
STRINGi10090.ENSMUSP00000020312.

Protein family/group databases

TCDBi1.A.77.1.1. the mg(2+)/ca(2+) uniporter (mcu) family.

PTM databases

iPTMnetiQ3UMR5.
PhosphoSitePlusiQ3UMR5.
SwissPalmiQ3UMR5.

Proteomic databases

EPDiQ3UMR5.
MaxQBiQ3UMR5.
PaxDbiQ3UMR5.
PeptideAtlasiQ3UMR5.
PRIDEiQ3UMR5.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000009791; ENSMUSP00000009791; ENSMUSG00000009647. [Q3UMR5-2]
ENSMUST00000020312; ENSMUSP00000020312; ENSMUSG00000009647. [Q3UMR5-1]
GeneIDi215999.
KEGGimmu:215999.
UCSCiuc007fds.3. mouse. [Q3UMR5-2]
uc007fdt.3. mouse. [Q3UMR5-1]

Organism-specific databases

CTDi90550.
MGIiMGI:3026965. Mcu.

Phylogenomic databases

eggNOGiKOG2966. Eukaryota.
ENOG410Y3YU. LUCA.
GeneTreeiENSGT00390000004496.
HOVERGENiHBG060246.
InParanoidiQ3UMR5.
OMAiGAVYCST.
OrthoDBiEOG091G092C.
PhylomeDBiQ3UMR5.
TreeFamiTF314435.

Miscellaneous databases

PROiQ3UMR5.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000009647.
CleanExiMM_CCDC109A.
ExpressionAtlasiQ3UMR5. baseline and differential.
GenevisibleiQ3UMR5. MM.

Family and domain databases

InterProiIPR006769. Coiled-coil-dom_prot_109_C.
[Graphical view]
PfamiPF04678. MCU. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMCU_MOUSE
AccessioniPrimary (citable) accession number: Q3UMR5
Secondary accession number(s): B2RTD1, Q3TTK3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 3, 2007
Last sequence update: April 3, 2007
Last modified: November 2, 2016
This is version 90 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.