MCU_DROME
ID MCU_DROME Reviewed; 366 AA.
AC Q8IQ70; E1NZC4; M9NF23; Q7KU70; X2JAQ2;
DT 07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 2.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Calcium uniporter protein, mitochondrial {ECO:0000305};
DE AltName: Full=Mitochondrial calcium uniporter {ECO:0000303|PubMed:27568554, ECO:0000312|FlyBase:FBgn0042185};
DE Flags: Precursor;
GN Name=MCU {ECO:0000303|PubMed:27568554, ECO:0000312|FlyBase:FBgn0042185};
GN ORFNames=CG18769 {ECO:0000312|FlyBase:FBgn0042185};
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley;
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=Berkeley; TISSUE=Embryo, and Head;
RA Celniker S., Carlson J., Wan K., Pfeiffer B., Frise E., George R.,
RA Hoskins R., Stapleton M., Pacleb J., Park S., Svirskas R., Smith E., Yu C.,
RA Rubin G.;
RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP ASP-260 AND GLU-263.
RX PubMed=27568554; DOI=10.1016/j.celrep.2016.08.017;
RA Drago I., Davis R.L.;
RT "Inhibiting the Mitochondrial Calcium Uniporter during Development Impairs
RT Memory in Adult Drosophila.";
RL Cell Rep. 16:2763-2776(2016).
RN [5]
RP FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP 260-ASP--GLU-263.
RX PubMed=28726639; DOI=10.1074/jbc.m116.765578;
RA Choi S., Quan X., Bang S., Yoo H., Kim J., Park J., Park K.S., Chung J.;
RT "Mitochondrial calcium uniporter in Drosophila transfers calcium between
RT the endoplasmic reticulum and mitochondria in oxidative stress-induced cell
RT death.";
RL J. Biol. Chem. 292:14473-14485(2017).
CC -!- FUNCTION: Mitochondrial inner membrane calcium uniporter that mediates
CC calcium uptake into mitochondria (PubMed:28726639). Constitutes a pore-
CC forming and calcium-conducting subunit (PubMed:28726639). Mitochondrial
CC calcium homeostasis plays key roles in cellular physiology and
CC regulates cell bioenergetics, cytoplasmic calcium signals and
CC activation of cell death pathways (PubMed:28726639). Together with
CC Itpr, has a role in oxidative stress-induced ER-mitochondria calcium
CC transfer (PubMed:28726639). During pupation, required for memory
CC function in mushroom body neurons (PubMed:27568554).
CC {ECO:0000269|PubMed:27568554, ECO:0000269|PubMed:28726639}.
CC -!- ACTIVITY REGULATION: Inhibited by ruthenium red or its derivative
CC Ru360. {ECO:0000250|UniProtKB:Q8NE86}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:27568554}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:27568554}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=A {ECO:0000312|FlyBase:FBgn0042185}, B
CC {ECO:0000312|FlyBase:FBgn0042185}, C {ECO:0000312|FlyBase:FBgn0042185},
CC D {ECO:0000312|FlyBase:FBgn0042185};
CC IsoId=Q8IQ70-1; Sequence=Displayed;
CC Name=2; Synonyms=G {ECO:0000312|FlyBase:FBgn0042185};
CC IsoId=Q8IQ70-2; Sequence=VSP_058493;
CC Name=3; Synonyms=E {ECO:0000312|FlyBase:FBgn0042185};
CC IsoId=Q8IQ70-3; Sequence=VSP_058492;
CC Name=4; Synonyms=H {ECO:0000312|FlyBase:FBgn0042185};
CC IsoId=Q8IQ70-4; Sequence=VSP_058494;
CC Name=5; Synonyms=I {ECO:0000312|FlyBase:FBgn0042185};
CC IsoId=Q8IQ70-5; Sequence=VSP_058495;
CC -!- TISSUE SPECIFICITY: Expressed throughout development, from embryo to
CC adult stage (at protein level). {ECO:0000269|PubMed:28726639}.
CC -!- DOMAIN: Forms a well-packed pentamer with an overall cylindrical shape.
CC The inner core of the pentamer is formed with the second transmembrane
CC region and the second coiled-coil region: while the transmembrane
CC regions pack into a five-helix bundle having a largely polar pore
CC across the membrane, the coiled-coil outside the membrane forms a
CC pentamer with a hydrophobic core. The inner core is wrapped by the
CC first transmembrane region through contacts between the first and the
CC second transmembrane regions. The second transmembrane is followed by
CC the inner juxtamembrane region (IJMH) that orients at a wide angle
CC relative to the second transmembrane. The two core domains are held
CC together on the periphery by the outer juxtamembrane helix (OJMH).
CC {ECO:0000250|UniProtKB:Q21121}.
CC -!- DOMAIN: The critical DXXE motif connecting the transmembrane regions
CC forms a pentameric barrel that constitutes the mouth of the pore.
CC Inside the barrel, two acidic residues are in position to form two
CC carboxylate rings. {ECO:0000250|UniProtKB:Q21121}.
CC -!- DISRUPTION PHENOTYPE: Mitochondrial calcium uptake defects
CC (PubMed:28726639). RNAi-mediated knockdown in neurons and mushroom body
CC neurons, from third instar larva to pupation stage, results in impaired
CC mitochondrial calcium entry, decreased synaptic vesicle content,
CC increased mushroom body neuron length and field volume which lead to
CC decreased intermediate-term memory after conditioning
CC (PubMed:27568554). Does not affect olfactory learning
CC (PubMed:27568554). {ECO:0000269|PubMed:27568554,
CC ECO:0000269|PubMed:28726639}.
CC -!- SIMILARITY: Belongs to the MCU (TC 1.A.77) family. {ECO:0000305}.
CC -!- CAUTION: It is unclear whether the absence of MCU causes lethality
CC (PubMed:28726639, PubMed:27568554). According to a report based on a
CC genetic knockout, it is viable (PubMed:28726639). According to a report
CC based on RNAi-mediated knockdown, it is lethal (PubMed:27568554).
CC {ECO:0000269|PubMed:27568554, ECO:0000269|PubMed:28726639}.
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DR EMBL; AE014296; AAG22325.2; -; Genomic_DNA.
DR EMBL; AE014296; AAN12082.2; -; Genomic_DNA.
DR EMBL; AE014296; AAN12083.2; -; Genomic_DNA.
DR EMBL; AE014296; AAS65071.1; -; Genomic_DNA.
DR EMBL; AE014296; AAS65072.1; -; Genomic_DNA.
DR EMBL; AE014296; AAS65073.2; -; Genomic_DNA.
DR EMBL; AE014296; AFH04318.1; -; Genomic_DNA.
DR EMBL; AE014296; AHN57979.1; -; Genomic_DNA.
DR EMBL; AY051736; AAK93160.1; -; mRNA.
DR EMBL; AY122129; AAM52641.1; -; mRNA.
DR EMBL; BT125673; ADN90233.1; -; mRNA.
DR RefSeq; NP_001246647.1; NM_001259718.1. [Q8IQ70-4]
DR RefSeq; NP_001286954.1; NM_001300025.1. [Q8IQ70-5]
DR RefSeq; NP_652706.3; NM_144449.4. [Q8IQ70-1]
DR RefSeq; NP_729173.1; NM_168169.3. [Q8IQ70-1]
DR RefSeq; NP_729174.2; NM_168170.2. [Q8IQ70-1]
DR RefSeq; NP_996002.2; NM_206280.2. [Q8IQ70-2]
DR RefSeq; NP_996003.1; NM_206281.2. [Q8IQ70-3]
DR RefSeq; NP_996004.1; NM_206282.2. [Q8IQ70-1]
DR AlphaFoldDB; Q8IQ70; -.
DR SMR; Q8IQ70; -.
DR IntAct; Q8IQ70; 64.
DR PRIDE; Q8IQ70; -.
DR DNASU; 59223; -.
DR EnsemblMetazoa; FBtr0076970; FBpp0076679; FBgn0042185. [Q8IQ70-1]
DR EnsemblMetazoa; FBtr0076971; FBpp0076680; FBgn0042185. [Q8IQ70-1]
DR EnsemblMetazoa; FBtr0076972; FBpp0076681; FBgn0042185. [Q8IQ70-1]
DR EnsemblMetazoa; FBtr0076973; FBpp0076682; FBgn0042185. [Q8IQ70-1]
DR EnsemblMetazoa; FBtr0076974; FBpp0076683; FBgn0042185. [Q8IQ70-3]
DR EnsemblMetazoa; FBtr0307510; FBpp0300165; FBgn0042185. [Q8IQ70-2]
DR EnsemblMetazoa; FBtr0307511; FBpp0300166; FBgn0042185. [Q8IQ70-4]
DR EnsemblMetazoa; FBtr0344294; FBpp0310698; FBgn0042185. [Q8IQ70-5]
DR GeneID; 59223; -.
DR KEGG; dme:Dmel_CG18769; -.
DR UCSC; CG18769-RA; d. melanogaster. [Q8IQ70-1]
DR UCSC; CG18769-RB; d. melanogaster.
DR CTD; 90550; -.
DR FlyBase; FBgn0042185; MCU.
DR VEuPathDB; VectorBase:FBgn0042185; -.
DR eggNOG; KOG2966; Eukaryota.
DR GeneTree; ENSGT00940000168365; -.
DR InParanoid; Q8IQ70; -.
DR OMA; DDIYVEY; -.
DR PhylomeDB; Q8IQ70; -.
DR Reactome; R-DME-8949215; Mitochondrial calcium ion transport.
DR BioGRID-ORCS; 59223; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 59223; -.
DR PRO; PR:Q8IQ70; -.
DR Proteomes; UP000000803; Chromosome 3L.
DR Bgee; FBgn0042185; Expressed in oviduct (Drosophila) and 20 other tissues.
DR ExpressionAtlas; Q8IQ70; baseline and differential.
DR Genevisible; Q7KU70; DM.
DR GO; GO:0031305; C:integral component of mitochondrial inner membrane; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; HDA:FlyBase.
DR GO; GO:1990246; C:uniplex complex; ISS:FlyBase.
DR GO; GO:0005262; F:calcium channel activity; ISS:FlyBase.
DR GO; GO:0015292; F:uniporter activity; ISS:FlyBase.
DR GO; GO:0007615; P:anesthesia-resistant memory; IMP:FlyBase.
DR GO; GO:0036444; P:calcium import into the mitochondrion; IMP:FlyBase.
DR GO; GO:0072375; P:medium-term memory; IMP:FlyBase.
DR GO; GO:0051560; P:mitochondrial calcium ion homeostasis; IMP:FlyBase.
DR GO; GO:0006851; P:mitochondrial calcium ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0006979; P:response to oxidative stress; IMP:UniProtKB.
DR InterPro; IPR006769; MCU_C.
DR InterPro; IPR039055; MCU_fam.
DR PANTHER; PTHR13462; PTHR13462; 1.
DR Pfam; PF04678; MCU; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Calcium channel; Calcium transport;
KW Coiled coil; Ion channel; Ion transport; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Reference proteome; Transit peptide;
KW Transmembrane; Transmembrane helix; Transport.
FT TRANSIT 1..53
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 54..366
FT /note="Calcium uniporter protein, mitochondrial"
FT /evidence="ECO:0000255"
FT /id="PRO_0000437213"
FT TOPO_DOM 54..232
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000250|UniProtKB:Q8NE86"
FT TRANSMEM 233..255
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 256..264
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000250|UniProtKB:Q8NE86"
FT TRANSMEM 265..284
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 285..366
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000250|UniProtKB:Q8NE86"
FT REGION 215..233
FT /note="Outer juxtamembrane helix (OJMH)"
FT /evidence="ECO:0000250|UniProtKB:Q21121"
FT REGION 282..291
FT /note="Inner juxtamembrane helix (IJMH)"
FT /evidence="ECO:0000250|UniProtKB:Q21121"
FT REGION 346..366
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 197..226
FT /evidence="ECO:0000255"
FT COILED 313..335
FT /evidence="ECO:0000255"
FT MOTIF 260..263
FT /note="DXXE"
FT /evidence="ECO:0000269|PubMed:28726639"
FT VAR_SEQ 1..81
FT /note="Missing (in isoform 3)"
FT /id="VSP_058492"
FT VAR_SEQ 71
FT /note="G -> GDITRLTLAELRTRLKALGLSAAGRKQVLVERLTRSTTCSATTLPRT
FT TGSNLSPEVFIGGLVNNSNTTSEPKNTVQQN (in isoform 2)"
FT /id="VSP_058493"
FT VAR_SEQ 71
FT /note="G -> GGHSSSQHVDEQAGCDDKIREKKSKSNHCLVKYRKGDQETEKGTNPC
FT GAQEFKESNSFAGTQVHSLKKRIKNRKIKKKLILNRKKKKKKTCN (in isoform
FT 4)"
FT /id="VSP_058494"
FT VAR_SEQ 72
FT /note="Missing (in isoform 5)"
FT /id="VSP_058495"
FT MUTAGEN 260..263
FT /note="DIME->NIMQ: Disrupts DXXE motif. Fails to rescue
FT phenotype of genetic knockout."
FT /evidence="ECO:0000269|PubMed:28726639"
FT MUTAGEN 260
FT /note="D->Q: In mushroom body neurons impairs mitochondrial
FT calcium entry and decreases intermediate-term memory after
FT conditioning; when associated with Q-263."
FT /evidence="ECO:0000269|PubMed:27568554"
FT MUTAGEN 263
FT /note="E->Q: In mushroom body neurons impairs mitochondrial
FT calcium entry and decreases intermediate-term memory after
FT conditioning; when associated with Q-260."
FT /evidence="ECO:0000269|PubMed:27568554"
SQ SEQUENCE 366 AA; 42478 MW; B5AB29FAA90D15FD CRC64;
MSRNRAAMVS AFRLFLRPAT TTTHRSLALR LAPGTTFALH LRPCHELQQH RSFASTAEDG
ETDKHKKPTT GEDIYVEYVN GMPHMTVRLP SRNELCQFAL KPISHNVGDL LAMLRAEDRG
IDRAAVINKH GVRIASSCTI ESLLDDSFSI QINNRTLDVN PPKRDKVTLE SMDKVGDVRK
VIAQLYEAFN VGEYQLEKSN QLAKELETLR YELEPLEEKK LELSKKAARR TNFMTWMGLG
LMSVQFGILA RLTWWEYSWD IMEPVTYFVT YGTTMAMYAY YCVTKREYMM EDVKNREFSL
SLYRNAKKVQ FDVEHYNELK RKSAELEYNL RRINDPLNMQ LPSHLVRTQE NTPPTLTEEK
AERKYT
