S2512_HUMAN
ID S2512_HUMAN Reviewed; 678 AA.
AC O75746; B3KR64; Q96AM8;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 2.
DT 03-AUG-2022, entry version 202.
DE RecName: Full=Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial {ECO:0000305|PubMed:9722566};
DE AltName: Full=Araceli hiperlarga {ECO:0000303|PubMed:9722566};
DE Short=Aralar {ECO:0000303|PubMed:9722566};
DE Short=Aralar1 {ECO:0000303|PubMed:11566871};
DE AltName: Full=Mitochondrial aspartate glutamate carrier 1 {ECO:0000303|PubMed:19641205};
DE AltName: Full=Solute carrier family 25 member 12 {ECO:0000312|HGNC:HGNC:10982};
GN Name=SLC25A12 {ECO:0000312|HGNC:HGNC:10982};
GN Synonyms=AGC1 {ECO:0000303|PubMed:19641205},
GN ARALAR1 {ECO:0000303|PubMed:10642534};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND TOPOLOGY.
RC TISSUE=Heart;
RX PubMed=9722566; DOI=10.1074/jbc.273.36.23327;
RA Del Arco A., Satrustegui J.;
RT "Molecular cloning of Aralar, a new member of the mitochondrial carrier
RT superfamily that binds calcium and is present in human muscle and brain.";
RL J. Biol. Chem. 273:23327-23334(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TRANSPORTER ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP AND TOPOLOGY.
RC TISSUE=Heart;
RX PubMed=11566871; DOI=10.1093/emboj/20.18.5060;
RA Palmieri L., Pardo B., Lasorsa F.M., del Arco A., Kobayashi K., Iijima M.,
RA Runswick M.J., Walker J.E., Saheki T., Satrustegui J., Palmieri F.;
RT "Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters
RT in mitochondria.";
RL EMBO J. 20:5060-5069(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Caudate nucleus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=10369257; DOI=10.1038/9667;
RA Kobayashi K., Sinasac D.S., Iijima M., Boright A.P., Begum L., Lee J.R.,
RA Yasuda T., Ikeda S., Hirano R., Terazono H., Crackower M.A., Kondo I.,
RA Tsui L.-C., Scherer S.W., Saheki T.;
RT "The gene mutated in adult-onset type II citrullinaemia encodes a putative
RT mitochondrial carrier protein.";
RL Nat. Genet. 22:159-163(1999).
RN [8]
RP NOMENCLATURE.
RX PubMed=10642534; DOI=10.1042/0264-6021:3450725;
RA Del Arco A., Agudo M., Satrustegui J.;
RT "Characterization of a second member of the subfamily of calcium-binding
RT mitochondrial carriers expressed in human non-excitable tissues.";
RL Biochem. J. 345:725-732(2000).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [11]
RP ACETYLATION AT ALA-2, AND CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=25489052; DOI=10.1093/hmg/ddu611;
RA Myklebust L.M., Van Damme P., Stoeve S.I., Doerfel M.J., Abboud A.,
RA Kalvik T.V., Grauffel C., Jonckheere V., Wu Y., Swensen J., Kaasa H.,
RA Liszczak G., Marmorstein R., Reuter N., Lyon G.J., Gevaert K., Arnesen T.;
RT "Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-
RT acetylation defects.";
RL Hum. Mol. Genet. 24:1956-1976(2015).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [13]
RP VARIANT DEE39 ARG-590, CHARACTERIZATION OF VARIANT DEE39 ARG-590, FUNCTION,
RP TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=19641205; DOI=10.1056/nejmoa0900591;
RA Wibom R., Lasorsa F.M., Tohonen V., Barbaro M., Sterky F.H., Kucinski T.,
RA Naess K., Jonsson M., Pierri C.L., Palmieri F., Wedell A.;
RT "AGC1 deficiency associated with global cerebral hypomyelination.";
RL N. Engl. J. Med. 361:489-495(2009).
RN [14]
RP ERRATUM OF PUBMED:19641205.
RA Wibom R., Lasorsa F.M., Tohonen V., Barbaro M., Sterky F.H., Kucinski T.,
RA Naess K., Jonsson M., Pierri C.L., Palmieri F., Wedell A.;
RL N. Engl. J. Med. 361:731-731(2009).
RN [15]
RP VARIANT DEE39 GLN-353, CHARACTERIZATION OF VARIANT DEE39 GLN-353, FUNCTION,
RP TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=24515575; DOI=10.1007/8904_2013_287;
RA Falk M.J., Li D., Gai X., McCormick E., Place E., Lasorsa F.M.,
RA Otieno F.G., Hou C., Kim C.E., Abdel-Magid N., Vazquez L., Mentch F.D.,
RA Chiavacci R., Liang J., Liu X., Jiang H., Giannuzzi G., Marsh E.D.,
RA Yiran G., Tian L., Palmieri F., Hakonarson H.;
RT "AGC1 deficiency causes infantile epilepsy, abnormal myelination, and
RT reduced n-acetylaspartate.";
RL JIMD Rep. 14:77-85(2014).
RN [16] {ECO:0007744|PDB:4P5X, ECO:0007744|PDB:4P60}
RP X-RAY CRYSTALLOGRAPHY (2.26 ANGSTROMS) OF 2-311 OF HOMODIMER IN COMPLEX
RP WITH CALCIUM, SUBUNIT, CALCIUM-BINDING, AND DOMAINS.
RX PubMed=25410934; DOI=10.1038/ncomms6491;
RA Thangaratnarajah C., Ruprecht J.J., Kunji E.R.;
RT "Calcium-induced conformational changes of the regulatory domain of human
RT mitochondrial aspartate/glutamate carriers.";
RL Nat. Commun. 5:5491-5491(2014).
CC -!- FUNCTION: Mitochondrial electrogenic aspartate/glutamate antiporter
CC that favors efflux of aspartate and entry of glutamate and proton
CC within the mitochondria as part of the malate-aspartate shuttle
CC (PubMed:11566871, PubMed:19641205, PubMed:24515575). Also mediates the
CC uptake of L-cysteinesulfinate by mitochondria in exchange of L-
CC glutamate and proton. Can also exchange L-cysteinesulfinate with
CC aspartate in their anionic form without any proton translocation
CC (PubMed:11566871). {ECO:0000269|PubMed:11566871,
CC ECO:0000269|PubMed:19641205, ECO:0000269|PubMed:24515575}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(out) + L-aspartate(in) + L-glutamate(out) = H(+)(in) + L-
CC aspartate(out) + L-glutamate(in); Xref=Rhea:RHEA:70783,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29985, ChEBI:CHEBI:29991;
CC Evidence={ECO:0000269|PubMed:11566871, ECO:0000269|PubMed:19641205,
CC ECO:0000269|PubMed:24515575};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3-sulfino-L-alanine(out) + H(+)(in) + L-glutamate(in) = 3-
CC sulfino-L-alanine(in) + H(+)(out) + L-glutamate(out);
CC Xref=Rhea:RHEA:70967, ChEBI:CHEBI:15378, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:61085; Evidence={ECO:0000269|PubMed:11566871};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3-sulfino-L-alanine(out) + L-aspartate(in) = 3-sulfino-L-
CC alanine(in) + L-aspartate(out); Xref=Rhea:RHEA:70975,
CC ChEBI:CHEBI:29991, ChEBI:CHEBI:61085;
CC Evidence={ECO:0000250|UniProtKB:F1LX07};
CC -!- ACTIVITY REGULATION: Activated by calcium-binding in the mitochondrial
CC intermembrane space (PubMed:11566871). Inhibited by pyridoxal 5'-
CC phosphate, bathophenathroline, mercurials, diethyl pyrocarbonate and N-
CC ethylmaleimide (PubMed:11566871). {ECO:0000269|PubMed:11566871}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=24.7 umol/min/g enzyme toward L-aspartate
CC {ECO:0000269|PubMed:11566871};
CC -!- SUBUNIT: Homodimer (via N-terminus). {ECO:0000269|PubMed:25410934}.
CC -!- INTERACTION:
CC O75746; Q7Z434: MAVS; NbExp=3; IntAct=EBI-1047585, EBI-995373;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:11566871, ECO:0000269|PubMed:19641205,
CC ECO:0000269|PubMed:24515575, ECO:0000269|PubMed:9722566}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:11566871}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O75746-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O75746-2; Sequence=VSP_054469;
CC -!- TISSUE SPECIFICITY: Expressed predominantly in the heart and skeletal
CC muscle, weakly in brain and kidney. {ECO:0000269|PubMed:10369257,
CC ECO:0000269|PubMed:9722566}.
CC -!- DOMAIN: The EF-hand 2 domain within the regulatory N-terminal domain
CC binds one calcium in the mitochondrial intermembrane space. Calcium
CC triggers the binding of the regulatory N-terminal domain to the C-
CC terminal domain, opening a vestibule which allows the substrates to be
CC translocated through the carrier domain. In the absence of calcium, the
CC linker loop domain may close the vestibule and prevent substrates from
CC entering the carrier domain. {ECO:0000269|PubMed:25410934}.
CC -!- DISEASE: Developmental and epileptic encephalopathy 39 (DEE39)
CC [MIM:612949]: A form of epileptic encephalopathy, a heterogeneous group
CC of severe early-onset epilepsies characterized by refractory seizures,
CC neurodevelopmental impairment, and poor prognosis. Development is
CC normal prior to seizure onset, after which cognitive and motor delays
CC become apparent. DEE39 is characterized by global hypomyelination of
CC the central nervous system, with the gray matter appearing relatively
CC unaffected. Inheritance is autosomal recessive.
CC {ECO:0000269|PubMed:19641205, ECO:0000269|PubMed:24515575}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family.
CC {ECO:0000305}.
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DR EMBL; Y14494; CAA74834.1; -; mRNA.
DR EMBL; AJ496568; CAD43090.1; -; mRNA.
DR EMBL; AK091071; BAG52276.1; -; mRNA.
DR EMBL; AC015976; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC068039; AAY24134.1; -; Genomic_DNA.
DR EMBL; AC114745; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471058; EAX11196.1; -; Genomic_DNA.
DR EMBL; BC016932; AAH16932.1; -; mRNA.
DR CCDS; CCDS33327.1; -. [O75746-1]
DR RefSeq; NP_003696.2; NM_003705.4. [O75746-1]
DR PDB; 4P5X; X-ray; 2.26 A; A=2-311.
DR PDB; 4P60; X-ray; 2.40 A; A/B=2-311.
DR PDBsum; 4P5X; -.
DR PDBsum; 4P60; -.
DR AlphaFoldDB; O75746; -.
DR SMR; O75746; -.
DR BioGRID; 114164; 224.
DR IntAct; O75746; 61.
DR MINT; O75746; -.
DR STRING; 9606.ENSP00000388658; -.
DR DrugBank; DB00128; Aspartic acid.
DR DrugCentral; O75746; -.
DR TCDB; 2.A.29.14.1; the mitochondrial carrier (mc) family.
DR GlyGen; O75746; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O75746; -.
DR PhosphoSitePlus; O75746; -.
DR SwissPalm; O75746; -.
DR BioMuta; SLC25A12; -.
DR EPD; O75746; -.
DR jPOST; O75746; -.
DR MassIVE; O75746; -.
DR MaxQB; O75746; -.
DR PaxDb; O75746; -.
DR PeptideAtlas; O75746; -.
DR PRIDE; O75746; -.
DR ProteomicsDB; 3583; -.
DR ProteomicsDB; 50177; -. [O75746-1]
DR Antibodypedia; 33855; 229 antibodies from 26 providers.
DR DNASU; 8604; -.
DR Ensembl; ENST00000422440.7; ENSP00000388658.2; ENSG00000115840.14. [O75746-1]
DR GeneID; 8604; -.
DR KEGG; hsa:8604; -.
DR MANE-Select; ENST00000422440.7; ENSP00000388658.2; NM_003705.5; NP_003696.2.
DR UCSC; uc002uhh.4; human. [O75746-1]
DR CTD; 8604; -.
DR DisGeNET; 8604; -.
DR GeneCards; SLC25A12; -.
DR HGNC; HGNC:10982; SLC25A12.
DR HPA; ENSG00000115840; Tissue enhanced (skeletal).
DR MalaCards; SLC25A12; -.
DR MIM; 603667; gene.
DR MIM; 612949; phenotype.
DR neXtProt; NX_O75746; -.
DR OpenTargets; ENSG00000115840; -.
DR Orphanet; 353217; Epileptic encephalopathy with global cerebral demyelination.
DR PharmGKB; PA35858; -.
DR VEuPathDB; HostDB:ENSG00000115840; -.
DR eggNOG; KOG0751; Eukaryota.
DR GeneTree; ENSGT00940000155963; -.
DR HOGENOM; CLU_014931_3_0_1; -.
DR InParanoid; O75746; -.
DR OMA; DWDCEWA; -.
DR OrthoDB; 1007928at2759; -.
DR PhylomeDB; O75746; -.
DR TreeFam; TF313209; -.
DR PathwayCommons; O75746; -.
DR Reactome; R-HSA-1268020; Mitochondrial protein import.
DR Reactome; R-HSA-70263; Gluconeogenesis.
DR Reactome; R-HSA-8963693; Aspartate and asparagine metabolism.
DR SignaLink; O75746; -.
DR SIGNOR; O75746; -.
DR BioGRID-ORCS; 8604; 9 hits in 1076 CRISPR screens.
DR ChiTaRS; SLC25A12; human.
DR GeneWiki; SLC25A12; -.
DR GenomeRNAi; 8604; -.
DR Pharos; O75746; Tbio.
DR PRO; PR:O75746; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; O75746; protein.
DR Bgee; ENSG00000115840; Expressed in biceps brachii and 202 other tissues.
DR ExpressionAtlas; O75746; baseline and differential.
DR Genevisible; O75746; HS.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0000514; F:3-sulfino-L-alanine: proton, glutamate antiporter activity; IDA:UniProtKB.
DR GO; GO:0015172; F:acidic amino acid transmembrane transporter activity; TAS:Reactome.
DR GO; GO:0000515; F:aspartate:glutamate, proton antiporter activity; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0015183; F:L-aspartate transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0005313; F:L-glutamate transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0022857; F:transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0009066; P:aspartate family amino acid metabolic process; TAS:Reactome.
DR GO; GO:0015810; P:aspartate transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006094; P:gluconeogenesis; TAS:Reactome.
DR GO; GO:0006537; P:glutamate biosynthetic process; IEA:Ensembl.
DR GO; GO:0015813; P:L-glutamate transmembrane transport; IDA:UniProtKB.
DR GO; GO:0043490; P:malate-aspartate shuttle; IDA:UniProtKB.
DR GO; GO:1904024; P:negative regulation of glucose catabolic process to lactate via pyruvate; IEA:Ensembl.
DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IEA:Ensembl.
DR GO; GO:0010907; P:positive regulation of glucose metabolic process; IEA:Ensembl.
DR GO; GO:0031643; P:positive regulation of myelination; IEA:Ensembl.
DR GO; GO:0051592; P:response to calcium ion; IDA:UniProtKB.
DR Gene3D; 1.50.40.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR002067; Mit_carrier.
DR InterPro; IPR018108; Mitochondrial_sb/sol_carrier.
DR InterPro; IPR023395; Mt_carrier_dom_sf.
DR Pfam; PF00153; Mito_carr; 3.
DR PRINTS; PR00926; MITOCARRIER.
DR SMART; SM00054; EFh; 3.
DR SUPFAM; SSF103506; SSF103506; 1.
DR SUPFAM; SSF47473; SSF47473; 2.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 2.
DR PROSITE; PS50920; SOLCAR; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Calcium; Disease variant;
KW Membrane; Metal-binding; Mitochondrion; Mitochondrion inner membrane;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:25489052,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..678
FT /note="Electrogenic aspartate/glutamate antiporter
FT SLC25A12, mitochondrial"
FT /id="PRO_0000090598"
FT TOPO_DOM 2..329
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000269|PubMed:11566871"
FT TRANSMEM 330..347
FT /note="Helical; Name=1"
FT /evidence="ECO:0000305|PubMed:9722566"
FT TOPO_DOM 348..390
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305|PubMed:11566871"
FT TRANSMEM 391..410
FT /note="Helical; Name=2"
FT /evidence="ECO:0000305|PubMed:9722566"
FT TOPO_DOM 411..433
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305|PubMed:11566871"
FT TRANSMEM 434..447
FT /note="Helical; Name=3"
FT /evidence="ECO:0000305|PubMed:9722566"
FT TOPO_DOM 448..482
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305|PubMed:11566871"
FT TRANSMEM 483..502
FT /note="Helical; Name=4"
FT /evidence="ECO:0000305|PubMed:9722566"
FT TOPO_DOM 503..521
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305|PubMed:11566871"
FT TRANSMEM 522..539
FT /note="Helical; Name=5"
FT /evidence="ECO:0000305|PubMed:9722566"
FT TOPO_DOM 540..578
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305|PubMed:11566871"
FT TRANSMEM 579..598
FT /note="Helical; Name=6"
FT /evidence="ECO:0000305|PubMed:9722566"
FT TOPO_DOM 599..678
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305|PubMed:11566871"
FT DOMAIN 65..76
FT /note="EF-hand 1"
FT /evidence="ECO:0000305"
FT DOMAIN 86..121
FT /note="EF-hand 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT DOMAIN 125..155
FT /note="EF-hand 3"
FT /evidence="ECO:0000305"
FT DOMAIN 157..192
FT /note="EF-hand 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT REPEAT 324..416
FT /note="Solcar 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00282"
FT REPEAT 424..508
FT /note="Solcar 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00282"
FT REPEAT 516..604
FT /note="Solcar 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00282"
FT REGION 2..294
FT /note="Regulatory N-terminal domain"
FT /evidence="ECO:0000303|PubMed:25410934"
FT REGION 295..310
FT /note="Linker loop domain"
FT /evidence="ECO:0000303|PubMed:25410934"
FT REGION 320..612
FT /note="Carrier domain"
FT /evidence="ECO:0000303|PubMed:25410934"
FT REGION 613..675
FT /note="C-terminal domain"
FT /evidence="ECO:0000303|PubMed:25410934"
FT BINDING 65
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:25410934,
FT ECO:0007744|PDB:4P5X"
FT BINDING 67
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:25410934,
FT ECO:0007744|PDB:4P5X"
FT BINDING 69
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:25410934,
FT ECO:0007744|PDB:4P5X"
FT BINDING 71
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:25410934,
FT ECO:0007744|PDB:4P5X"
FT BINDING 76
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:25410934,
FT ECO:0007744|PDB:4P5X"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000269|PubMed:25489052,
FT ECO:0007744|PubMed:22814378"
FT VAR_SEQ 1..108
FT /note="MAVKVQTTKRGDPHELRNIFLQYASTEVDGERYMTPEDFVQRYLGLYNDPNS
FT NPKIVQLLAGVADQTKDGLISYQEFLAFESVLCAPDSMFIVAFQLFDKSGNGEVTF ->
FT M (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054469"
FT VARIANT 353
FT /note="R -> Q (in DEE39; decreased antiporter activity;
FT significant loss in ability to transport aspartate or
FT glutamate; no effect on localization to mitochondrial inner
FT membrane; no effect on protein abundance;
FT dbSNP:rs886037851)"
FT /evidence="ECO:0000269|PubMed:24515575"
FT /id="VAR_071976"
FT VARIANT 473
FT /note="R -> Q (in dbSNP:rs35565687)"
FT /id="VAR_047917"
FT VARIANT 590
FT /note="Q -> R (in DEE39; loss of antiporter activity;
FT unable to transport aspartate or glutamate; no effect on
FT localization to mitochondrial inner membrane; no effect on
FT protein abundance; dbSNP:rs121434396)"
FT /evidence="ECO:0000269|PubMed:19641205"
FT /id="VAR_063253"
FT CONFLICT 596..597
FT /note="VT -> AH (in Ref. 1; CAA74834)"
FT /evidence="ECO:0000305"
FT CONFLICT 600
FT /note="L -> V (in Ref. 1; CAA74834)"
FT /evidence="ECO:0000305"
FT HELIX 15..23
FT /evidence="ECO:0007829|PDB:4P5X"
FT STRAND 26..28
FT /evidence="ECO:0007829|PDB:4P5X"
FT STRAND 31..34
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 36..40
FT /evidence="ECO:0007829|PDB:4P5X"
FT TURN 41..43
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 54..64
FT /evidence="ECO:0007829|PDB:4P5X"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:4P60"
FT HELIX 74..84
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 89..98
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 108..117
FT /evidence="ECO:0007829|PDB:4P5X"
FT STRAND 128..130
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 131..137
FT /evidence="ECO:0007829|PDB:4P5X"
FT TURN 138..141
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 147..169
FT /evidence="ECO:0007829|PDB:4P5X"
FT STRAND 174..177
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 179..189
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 191..193
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 196..200
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 202..205
FT /evidence="ECO:0007829|PDB:4P5X"
FT TURN 206..210
FT /evidence="ECO:0007829|PDB:4P60"
FT STRAND 212..215
FT /evidence="ECO:0007829|PDB:4P60"
FT HELIX 216..227
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 229..238
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 250..257
FT /evidence="ECO:0007829|PDB:4P5X"
FT TURN 258..261
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 265..276
FT /evidence="ECO:0007829|PDB:4P5X"
FT STRAND 282..284
FT /evidence="ECO:0007829|PDB:4P5X"
FT HELIX 286..292
FT /evidence="ECO:0007829|PDB:4P5X"
FT STRAND 300..302
FT /evidence="ECO:0007829|PDB:4P60"
FT TURN 305..307
FT /evidence="ECO:0007829|PDB:4P60"
SQ SEQUENCE 678 AA; 74762 MW; D00A7D3D4244539F CRC64;
MAVKVQTTKR GDPHELRNIF LQYASTEVDG ERYMTPEDFV QRYLGLYNDP NSNPKIVQLL
AGVADQTKDG LISYQEFLAF ESVLCAPDSM FIVAFQLFDK SGNGEVTFEN VKEIFGQTII
HHHIPFNWDC EFIRLHFGHN RKKHLNYTEF TQFLQELQLE HARQAFALKD KSKSGMISGL
DFSDIMVTIR SHMLTPFVEE NLVSAAGGSI SHQVSFSYFN AFNSLLNNME LVRKIYSTLA
GTRKDVEVTK EEFAQSAIRY GQVTPLEIDI LYQLADLYNA SGRLTLADIE RIAPLAEGAL
PYNLAELQRQ QSPGLGRPIW LQIAESAYRF TLGSVAGAVG ATAVYPIDLV KTRMQNQRGS
GSVVGELMYK NSFDCFKKVL RYEGFFGLYR GLIPQLIGVA PEKAIKLTVN DFVRDKFTRR
DGSVPLPAEV LAGGCAGGSQ VIFTNPLEIV KIRLQVAGEI TTGPRVSALN VLRDLGIFGL
YKGAKACFLR DIPFSAIYFP VYAHCKLLLA DENGHVGGLN LLAAGAMAGV PAASLVTPAD
VIKTRLQVAA RAGQTTYSGV IDCFRKILRE EGPSAFWKGT AARVFRSSPQ FGVTLVTYEL
LQRWFYIDFG GLKPAGSEPT PKSRIADLPP ANPDHIGGYR LATATFAGIE NKFGLYLPKF
KSPSVAVVQP KAAVAATQ
