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Protein

Calcium uniporter protein, mitochondrial

Gene

MCU

Organism
Homo sapiens (Human)
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:21685888, PubMed:21685886, PubMed:23101630, PubMed:22904319, PubMed:23178883, PubMed:22829870, PubMed:22822213, PubMed:24332854, PubMed:23755363, PubMed:26341627). Constitutes the pore-forming and calcium-conducting subunit of the uniporter complex (uniplex) (PubMed:23755363). Activity is regulated by MICU1 and MICU2. At low Ca2+ levels MCU activity is down-regulated by MICU1 and MICU2; at higher Ca2+ levels MICU1 increases MCU activity (PubMed:24560927, PubMed:26903221). Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways. Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes (PubMed:22822213). 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:25603276). participates in mitochondrial permeability transition during ischemia-reperfusion injury (By similarity). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (PubMed:22904319, PubMed:22829870). Mitochondrial calcium uptake in skeletal muscle cells is involved in muscle size in adults (By similarity). Regulates synaptic vesicle endocytosis kinetics in central nerve terminal (By similarity). Involved in antigen processing and presentation (By similarity).By similarity13 Publications

Enzyme regulationi

Inhibited by ruthenium red or its derivative Ru360.1 Publication

GO - Molecular functioni

  • calcium channel activity Source: UniProtKB
  • uniporter activity Source: UniProtKB

GO - Biological processi

  • calcium ion transmembrane import into mitochondrion Source: UniProtKB
  • calcium-mediated signaling Source: UniProtKB
  • glucose homeostasis Source: UniProtKB
  • mitochondrial calcium ion transport Source: UniProtKB
  • positive regulation of insulin secretion Source: UniProtKB
  • positive regulation of mitochondrial calcium ion concentration Source: UniProtKB
  • protein complex oligomerization Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Calcium channel, Ion channel

Keywords - Biological processi

Calcium transport, Ion transport, Transport

Keywords - Ligandi

Calcium

Enzyme and pathway databases

BioCyciZFISH:ENSG00000156026-MONOMER.
ZFISH:MONOMER66-34413.

Names & Taxonomyi

Protein namesi
Recommended name:
Calcium uniporter protein, mitochondrial1 Publication
Short name:
HsMCU1 Publication
Alternative name(s):
Coiled-coil domain-containing protein 109ACurated
Gene namesi
Name:MCU1 PublicationImported
Synonyms:C10orf42Imported, CCDC109AImported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:23526. MCU.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini51 – 233Mitochondrial matrix1 PublicationAdd BLAST183
Transmembranei234 – 256HelicalSequence analysisAdd BLAST23
Topological domaini257 – 265Mitochondrial intermembrane1 Publication9
Transmembranei266 – 283HelicalSequence analysisAdd BLAST18
Topological domaini284 – 351Mitochondrial matrix1 Publication1 PublicationAdd BLAST68

GO - Cellular componenti

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

Keywords - Cellular componenti

Membrane, Mitochondrion, Mitochondrion inner membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi57S → A: Decreased MCU current; when associated with A-92. 1 Publication1
Mutagenesisi92S → A: Decreased MCU current; when associated with A-57. 1 Publication1
Mutagenesisi92S → A: Impairs Ca(2+) uptake, but has no effect on oligomerization and interaction with MCU1 and MCU2. 1 Publication1
Mutagenesisi180K → A: No effect on Ca(2+) uptake, oligomerization and interaction with MCU1 and MCU2. 1 Publication1
Mutagenesisi257E → A: According to a report, inhibits calcium uptake. According to a subsequent report, does not affect greatly calcium uptake. 2 Publications1
Mutagenesisi257E → S: Does not affect greatly calcium uptake. 1 Publication1
Mutagenesisi259S → A: Does not inhibit calcium uptake. Strongly reduced sensitivity to ruthenium red inhibition. 2 Publications1
Mutagenesisi259S → R: Prevents entrance of calcium into the pore. 1 Publication1
Mutagenesisi261 – 264DIME → AIMA: Dominant negative (DN) mutant; inhibits calcium uptake. Inhibits calcium channel activity. Expression of the dominant negative protein in mice, leads to mice that are incapable of physiological fight or flight heart rate acceleration. 3 Publications4
Mutagenesisi261D → E: Partially functional; does not completely abolish calcium channel activity. 1 Publication1
Mutagenesisi264E → D: Abolishes calcium channel activity. 1 Publication1

Organism-specific databases

DisGeNETi90550.
OpenTargetsiENSG00000156026.
PharmGKBiPA134888841.

Polymorphism and mutation databases

DMDMi74730222.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 50MitochondrionSequence analysisAdd BLAST50
ChainiPRO_000028297651 – 351Calcium uniporter protein, mitochondrialAdd BLAST301

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei57Phosphoserine; by CaMK21 Publication1
Modified residuei92Phosphoserine; by CaMK21 Publication1
Modified residuei332N6-acetyllysineBy similarity1

Post-translational modificationi

Phosphorylation by CaMK2 in heart leads to increased MCU current (PubMed:23051746, PubMed:25254481). The regulation of MCU by CaMK2 is however subject to discussion: another group was unable to reproduce these results (PubMed:25254480). Phosphorylated on tyrosines by PTK2B/PYK2, promoting oligomerization (PubMed:24800979).3 Publications1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ8NE86.
MaxQBiQ8NE86.
PaxDbiQ8NE86.
PeptideAtlasiQ8NE86.
PRIDEiQ8NE86.
TopDownProteomicsiQ8NE86-3. [Q8NE86-3]

PTM databases

iPTMnetiQ8NE86.
PhosphoSitePlusiQ8NE86.
SwissPalmiQ8NE86.

Expressioni

Inductioni

MCU transcripts are down-regulated by microRNA miR-25 (PubMed:23246404). Down-regulation by miR-25 may protect cardiomyocytes against oxidative damage in cardiomyocytes (PubMed:25764156).2 Publications

Gene expression databases

BgeeiENSG00000156026.
CleanExiHS_CCDC109A.
ExpressionAtlasiQ8NE86. baseline and differential.
GenevisibleiQ8NE86. HS.

Organism-specific databases

HPAiHPA016480.

Interactioni

Subunit structurei

Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1 (PubMed:24231807). Homooligomer (PubMed:21685886, PubMed:26341627). Forms a pentamer (By similarity). Heterooligomer with CCDC109B/MCUB; this inhibits channel activity (By similarity). Interacts with MICU1; MICU1 acts as an essential regulator for MCU (PubMed:21685886, PubMed:23101630, PubMed:23178883, PubMed:24332854, PubMed:26341627). Interacts with MCUR1 (PubMed:23178883, PubMed:26341627, PubMed:27184846, PubMed:26976564). Interacts with CCDC90B (PubMed:27184846). Interactions with MICU1 and MCUR1 are mutually exclusive (PubMed:23178883). Interacts with MICU2 (PubMed:26341627). Interacts with SLC25A23 (PubMed:24430870).By similarity9 Publications

Protein-protein interaction databases

BioGridi124733. 30 interactors.
DIPiDIP-60468N.
IntActiQ8NE86. 11 interactors.
MINTiMINT-8051705.
STRINGi9606.ENSP00000362144.

Structurei

Secondary structure

1351
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi76 – 80Combined sources5
Beta strandi83 – 88Combined sources6
Beta strandi91 – 93Combined sources3
Beta strandi97 – 100Combined sources4
Turni103 – 105Combined sources3
Helixi108 – 118Combined sources11
Beta strandi125 – 128Combined sources4
Beta strandi137 – 140Combined sources4
Helixi141 – 144Combined sources4
Beta strandi149 – 153Combined sources5
Beta strandi156 – 160Combined sources5
Helixi168 – 172Combined sources5

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4XSJX-ray1.80A75-165[»]
4XTBX-ray1.50A75-185[»]
5BZ6X-ray2.75A75-165[»]
5KUEX-ray1.50A72-189[»]
5KUGX-ray1.90A72-189[»]
5KUIX-ray2.70A72-189[»]
5KUJX-ray1.60A72-189[»]
ProteinModelPortaliQ8NE86.
SMRiQ8NE86.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni75 – 165N-terminal MCU domain1 PublicationAdd BLAST91
Regioni216 – 234Outer juxtamembrane helix (OJMH)By similarityAdd BLAST19
Regioni283 – 292Inner juxtamembrane helix (IJMH)By similarity10

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili192 – 223Sequence analysisAdd BLAST32
Coiled coili311 – 339Sequence analysisAdd BLAST29

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi261 – 264DXXEBy similarity4

Domaini

The N-terminal MCU 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.1 Publication
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.
HOGENOMiHOG000008081.
HOVERGENiHBG060246.
InParanoidiQ8NE86.
OMAiGAVYCST.
OrthoDBiEOG091G092C.
PhylomeDBiQ8NE86.
TreeFamiTF314435.

Family and domain databases

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

Sequences (3)i

Sequence statusi: Complete.

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

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8NE86-1) [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 LLLSSRGGGG GGAGGCGALT AGCFPGLGVS RHRQQQHHRT
60 70 80 90 100
VHQRIASWQN LGAVYCSTVV PSDDVTVVYQ NGLPVISVRL PSRRERCQFT
110 120 130 140 150
LKPISDSVGV FLRQLQEEDR GIDRVAIYSP DGVRVAASTG IDLLLLDDFK
160 170 180 190 200
LVINDLTYHV RPPKRDLLSH ENAATLNDVK TLVQQLYTTL CIEQHQLNKE
210 220 230 240 250
RELIERLEDL KEQLAPLEKV RIEISRKAEK RTTLVLWGGL AYMATQFGIL
260 270 280 290 300
ARLTWWEYSW DIMEPVTYFI TYGSAMAMYA YFVMTRQEYV YPEARDRQYL
310 320 330 340 350
LFFHKGAKKS RFDLEKYNQL KDAIAQAEMD LKRLRDPLQV HLPLRQIGEK

D
Length:351
Mass (Da):39,867
Last modified:October 1, 2002 - v1
Checksum:i50205D01055D66E4
GO
Isoform 2 (identifier: Q8NE86-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     166-219: DLLSHENAAT...LKEQLAPLEK → VEMGFCHVGQNGFELLTSSYLPASASQSAEIIA

Note: No experimental confirmation available.
Show »
Length:330
Mass (Da):36,996
Checksum:i56D458541240604A
GO
Isoform 3 (identifier: Q8NE86-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-50: MAAAAGRSLLLLLSSRGGGGGGAGGCGALTAGCFPGLGVSRHRQQQHHRT → M

Show »
Length:302
Mass (Da):35,159
Checksum:i65C6D99CD9D2D3FC
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti107S → P in BAG37900 (PubMed:14702039).Curated1
Sequence conflicti142D → Y in BAG37900 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0416871 – 50MAAAA…QHHRT → M in isoform 3. 1 PublicationAdd BLAST50
Alternative sequenceiVSP_024263166 – 219DLLSH…APLEK → VEMGFCHVGQNGFELLTSSY LPASASQSAEIIA in isoform 2. 1 PublicationAdd BLAST54

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK315519 mRNA. Translation: BAG37900.1.
AK128016 mRNA. Translation: BAG54619.1.
AC016542 Genomic DNA. No translation available.
AC069548 Genomic DNA. No translation available.
CH471083 Genomic DNA. Translation: EAW54461.1.
BC010682 mRNA. Translation: AAH10682.1.
BC034235 mRNA. Translation: AAH34235.1.
CCDSiCCDS59218.1. [Q8NE86-2]
CCDS59219.1. [Q8NE86-3]
CCDS7317.1. [Q8NE86-1]
RefSeqiNP_001257608.1. NM_001270679.1. [Q8NE86-2]
NP_001257609.1. NM_001270680.1. [Q8NE86-3]
NP_612366.1. NM_138357.2. [Q8NE86-1]
UniGeneiHs.591366.

Genome annotation databases

EnsembliENST00000357157; ENSP00000349680; ENSG00000156026. [Q8NE86-2]
ENST00000373053; ENSP00000362144; ENSG00000156026. [Q8NE86-1]
ENST00000536019; ENSP00000440913; ENSG00000156026. [Q8NE86-3]
GeneIDi90550.
KEGGihsa:90550.
UCSCiuc001jtc.3. human. [Q8NE86-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK315519 mRNA. Translation: BAG37900.1.
AK128016 mRNA. Translation: BAG54619.1.
AC016542 Genomic DNA. No translation available.
AC069548 Genomic DNA. No translation available.
CH471083 Genomic DNA. Translation: EAW54461.1.
BC010682 mRNA. Translation: AAH10682.1.
BC034235 mRNA. Translation: AAH34235.1.
CCDSiCCDS59218.1. [Q8NE86-2]
CCDS59219.1. [Q8NE86-3]
CCDS7317.1. [Q8NE86-1]
RefSeqiNP_001257608.1. NM_001270679.1. [Q8NE86-2]
NP_001257609.1. NM_001270680.1. [Q8NE86-3]
NP_612366.1. NM_138357.2. [Q8NE86-1]
UniGeneiHs.591366.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4XSJX-ray1.80A75-165[»]
4XTBX-ray1.50A75-185[»]
5BZ6X-ray2.75A75-165[»]
5KUEX-ray1.50A72-189[»]
5KUGX-ray1.90A72-189[»]
5KUIX-ray2.70A72-189[»]
5KUJX-ray1.60A72-189[»]
ProteinModelPortaliQ8NE86.
SMRiQ8NE86.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi124733. 30 interactors.
DIPiDIP-60468N.
IntActiQ8NE86. 11 interactors.
MINTiMINT-8051705.
STRINGi9606.ENSP00000362144.

PTM databases

iPTMnetiQ8NE86.
PhosphoSitePlusiQ8NE86.
SwissPalmiQ8NE86.

Polymorphism and mutation databases

DMDMi74730222.

Proteomic databases

EPDiQ8NE86.
MaxQBiQ8NE86.
PaxDbiQ8NE86.
PeptideAtlasiQ8NE86.
PRIDEiQ8NE86.
TopDownProteomicsiQ8NE86-3. [Q8NE86-3]

Protocols and materials databases

DNASUi90550.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000357157; ENSP00000349680; ENSG00000156026. [Q8NE86-2]
ENST00000373053; ENSP00000362144; ENSG00000156026. [Q8NE86-1]
ENST00000536019; ENSP00000440913; ENSG00000156026. [Q8NE86-3]
GeneIDi90550.
KEGGihsa:90550.
UCSCiuc001jtc.3. human. [Q8NE86-1]

Organism-specific databases

CTDi90550.
DisGeNETi90550.
GeneCardsiMCU.
HGNCiHGNC:23526. MCU.
HPAiHPA016480.
MIMi614197. gene.
neXtProtiNX_Q8NE86.
OpenTargetsiENSG00000156026.
PharmGKBiPA134888841.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2966. Eukaryota.
ENOG410Y3YU. LUCA.
GeneTreeiENSGT00390000004496.
HOGENOMiHOG000008081.
HOVERGENiHBG060246.
InParanoidiQ8NE86.
OMAiGAVYCST.
OrthoDBiEOG091G092C.
PhylomeDBiQ8NE86.
TreeFamiTF314435.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000156026-MONOMER.
ZFISH:MONOMER66-34413.

Miscellaneous databases

ChiTaRSiMCU. human.
GenomeRNAii90550.
PROiQ8NE86.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000156026.
CleanExiHS_CCDC109A.
ExpressionAtlasiQ8NE86. baseline and differential.
GenevisibleiQ8NE86. HS.

Family and domain databases

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

Entry informationi

Entry nameiMCU_HUMAN
AccessioniPrimary (citable) accession number: Q8NE86
Secondary accession number(s): B2RDF3, B3KXV7, Q96FL3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 3, 2007
Last sequence update: October 1, 2002
Last modified: November 30, 2016
This is version 112 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. 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.