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   27-MAR-2024, entry version 211.
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}, ARALAR1
GN   {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 with
CC       leukodystrophy (DEE39) [MIM:612949]: A form of epileptic
CC       encephalopathy, a heterogeneous group of severe early-onset epilepsies
CC       characterized by refractory seizures, neurodevelopmental impairment,
CC       and poor prognosis. Development is normal prior to seizure onset, after
CC       which cognitive and motor delays become apparent. DEE39 is
CC       characterized by global hypomyelination of the central nervous system,
CC       with the gray matter appearing relatively unaffected. Inheritance is
CC       autosomal recessive. {ECO:0000269|PubMed:19641205,
CC       ECO:0000269|PubMed:24515575}. Note=The disease is caused by variants
CC       affecting the gene represented in this 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; 240.
DR   IntAct; O75746; 64.
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; 9606-ENSP00000388658; -.
DR   PeptideAtlas; O75746; -.
DR   ProteomicsDB; 3583; -.
DR   ProteomicsDB; 50177; -. [O75746-1]
DR   Pumba; O75746; -.
DR   Antibodypedia; 33855; 267 antibodies from 26 providers.
DR   DNASU; 8604; -.
DR   Ensembl; ENST00000422440.7; ENSP00000388658.2; ENSG00000115840.14. [O75746-1]
DR   Ensembl; ENST00000709717.1; ENSP00000517838.1; ENSG00000292099.1. [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   AGR; HGNC:10982; -.
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; GPDAIPF; -.
DR   OrthoDB; 1220009at2759; -.
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 1157 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 204 other cell types or tissues.
DR   ExpressionAtlas; O75746; baseline and differential.
DR   GO; GO:0016020; C: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; EXP: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: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:0015813; P:L-glutamate transmembrane transport; IDA:UniProtKB.
DR   GO; GO:0043490; P:malate-aspartate shuttle; IDA:UniProtKB.
DR   GO; GO:0051592; P:response to calcium ion; IDA:UniProtKB.
DR   Gene3D; 1.10.238.10; EF-hand; 2.
DR   Gene3D; 1.50.40.10; Mitochondrial carrier domain; 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   PANTHER; PTHR45678:SF7; CALCIUM-BINDING MITOCHONDRIAL CARRIER PROTEIN ARALAR1; 1.
DR   PANTHER; PTHR45678; MITOCHONDRIAL 2-OXODICARBOXYLATE CARRIER 1-RELATED; 1.
DR   Pfam; PF00153; Mito_carr; 3.
DR   PRINTS; PR00926; MITOCARRIER.
DR   SMART; SM00054; EFh; 3.
DR   SUPFAM; SSF47473; EF-hand; 2.
DR   SUPFAM; SSF103506; Mitochondrial carrier; 1.
DR   PROSITE; PS00018; EF_HAND_1; 1.
DR   PROSITE; PS50222; EF_HAND_2; 2.
DR   PROSITE; PS50920; SOLCAR; 3.
DR   Genevisible; O75746; HS.
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
//