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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). Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways. Activity is regulated by MICU1 and MICU2 that stimulate and inhibit MCU activity, respectively. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes (By similarity).By similarity3 Publications

GO - Molecular functioni

  • calcium channel activity Source: UniProtKB
  • identical protein binding Source: IntAct
  • uniporter activity Source: MGI

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, mitochondrial
Alternative name(s):
Coiled-coil domain-containing protein 109A
Gene namesi
Name:Mcu
Synonyms:Ccdc109a
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)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini50 – 232183Mitochondrial matrixSequence analysisAdd
BLAST
Transmembranei233 – 25624HelicalSequence analysisAdd
BLAST
Topological domaini257 – 2648Mitochondrial intermembraneSequence analysis
Transmembranei265 – 28218HelicalSequence analysisAdd
BLAST
Topological domaini283 – 35068Mitochondrial matrixSequence analysisAdd
BLAST

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

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).2 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi251 – 2511R → W: Strongly reduces calcium channel activity; when associated with V-256. 1 Publication
Mutagenesisi256 – 2561E → V: Strongly reduces calcium channel activity; when associated with W-251. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transit peptidei1 – 4949MitochondrionSequence analysisAdd
BLAST
Chaini50 – 350301Calcium uniporter protein, mitochondrialPRO_0000282977Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei331 – 3311N6-acetyllysineCombined sources

Keywords - PTMi

Acetylation

Proteomic databases

EPDiQ3UMR5.
MaxQBiQ3UMR5.
PaxDbiQ3UMR5.
PeptideAtlasiQ3UMR5.
PRIDEiQ3UMR5.

PTM databases

iPTMnetiQ3UMR5.
PhosphoSiteiQ3UMR5.
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

BgeeiQ3UMR5.
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). Heterotetramer 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).By similarity2 Publications

Binary interactionsi

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

GO - Molecular functioni

  • identical protein binding Source: IntAct

Protein-protein interaction databases

IntActiQ3UMR5. 4 interactions.
STRINGi10090.ENSMUSP00000020312.

Structurei

3D structure databases

SMRiQ3UMR5. Positions 74-181.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni74 – 16491N-terminal MCU domainBy similarityAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili191 – 22030Sequence analysisAdd
BLAST
Coiled coili310 – 33829Sequence analysisAdd
BLAST

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

Sequence similaritiesi

Keywords - Domaini

Coiled coil, Transit peptide, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2966. Eukaryota.
ENOG410Y3YU. LUCA.
GeneTreeiENSGT00390000004496.
HOVERGENiHBG060246.
InParanoidiQ3UMR5.
OMAiGAVYCST.
OrthoDBiEOG7HF1JN.
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)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 149149Missing in isoform 2. 2 PublicationsVSP_024264Add
BLAST
Alternative sequencei150 – 16415LVIND…RPPKR → MILRPKQLFSAFTKQ in isoform 2. 2 PublicationsVSP_024265Add
BLAST

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]
XP_011241697.1. XM_011243395.1. [Q3UMR5-2]
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]
XP_011241697.1. XM_011243395.1. [Q3UMR5-2]
UniGeneiMm.296470.

3D structure databases

SMRiQ3UMR5. Positions 74-181.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ3UMR5. 4 interactions.
STRINGi10090.ENSMUSP00000020312.

Protein family/group databases

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

PTM databases

iPTMnetiQ3UMR5.
PhosphoSiteiQ3UMR5.
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.
OrthoDBiEOG7HF1JN.
PhylomeDBiQ3UMR5.
TreeFamiTF314435.

Miscellaneous databases

PROiQ3UMR5.
SOURCEiSearch...

Gene expression databases

BgeeiQ3UMR5.
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...

Publicationsi

« Hide 'large scale' publications
  1. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-224 (ISOFORM 1).
    Strain: C57BL/6J.
    Tissue: Lung and Testis.
  2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
    Tissue: Brain.
  4. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas and Spleen.
  5. "Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter."
    Baughman J.M., Perocchi F., Girgis H.S., Plovanich M., Belcher-Timme C.A., Sancak Y., Bao X.R., Strittmatter L., Goldberger O., Bogorad R.L., Koteliansky V., Mootha V.K.
    Nature 476:341-345(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  6. "A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter."
    De Stefani D., Raffaello A., Teardo E., Szabo I., Rizzuto R.
    Nature 476:336-340(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  7. "The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit."
    Raffaello A., De Stefani D., Sabbadin D., Teardo E., Merli G., Picard A., Checchetto V., Moro S., Szabo I., Rizzuto R.
    EMBO J. 32:2362-2376(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, MUTAGENESIS OF ARG-251 AND GLU-256, TISSUE SPECIFICITY.
  8. "The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter."
    Pan X., Liu J., Nguyen T., Liu C., Sun J., Teng Y., Fergusson M.M., Rovira I.I., Allen M., Springer D.A., Aponte A.M., Gucek M., Balaban R.S., Murphy E., Finkel T.
    Nat. Cell Biol. 15:1464-1472(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, FUNCTION.
  9. "MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling."
    Plovanich M., Bogorad R.L., Sancak Y., Kamer K.J., Strittmatter L., Li A.A., Girgis H.S., Kuchimanchi S., De Groot J., Speciner L., Taneja N., Oshea J., Koteliansky V., Mootha V.K.
    PLoS ONE 8:E55785-E55785(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION IN A COMPLEX WITH MICU1 AND MICU2, TISSUE SPECIFICITY.
  10. "Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways."
    Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B., Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.
    Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-331, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  11. Cited for: DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.

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: July 6, 2016
This is version 87 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.