ADT4_HUMAN
ID ADT4_HUMAN Reviewed; 315 AA.
AC Q9H0C2;
DT 21-AUG-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=ADP/ATP translocase 4 {ECO:0000305};
DE AltName: Full=ADP,ATP carrier protein 4 {ECO:0000303|PubMed:15670820};
DE AltName: Full=Adenine nucleotide translocator 4 {ECO:0000250|UniProtKB:Q3V132};
DE Short=ANT 4 {ECO:0000250|UniProtKB:Q3V132};
DE AltName: Full=Solute carrier family 25 member 31 {ECO:0000305};
DE AltName: Full=Sperm flagellar energy carrier protein {ECO:0000303|PubMed:17137571};
GN Name=SLC25A31 {ECO:0000312|HGNC:HGNC:25319};
GN Synonyms=AAC4 {ECO:0000303|PubMed:15670820},
GN ANT4 {ECO:0000250|UniProtKB:Q3V132}, SFEC {ECO:0000303|PubMed:17137571};
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], SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=15670820; DOI=10.1016/j.febslet.2004.12.034;
RA Dolce V., Scarcia P., Iacopetta D., Palmieri F.;
RT "A fourth ADP/ATP carrier isoform in man: identification, bacterial
RT expression, functional characterization and tissue distribution.";
RL FEBS Lett. 579:633-637(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=17137571; DOI=10.1016/j.ydbio.2006.10.004;
RA Kim Y.-H., Haidl G., Schaefer M., Egner U., Mandal A., Herr J.C.;
RT "Compartmentalization of a unique ADP/ATP carrier protein SFEC (sperm
RT flagellar energy carrier, AAC4) with glycolytic enzymes in the fibrous
RT sheath of the human sperm flagellar principal piece.";
RL Dev. Biol. 302:463-476(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
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].
RC TISSUE=Testis;
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=17681941; DOI=10.1074/jbc.m704386200;
RA Brower J.V., Rodic N., Seki T., Jorgensen M., Fliess N., Yachnis A.T.,
RA McCarrey J.R., Oh S.P., Terada N.;
RT "Evolutionarily conserved mammalian adenine nucleotide translocase 4 is
RT essential for spermatogenesis.";
RL J. Biol. Chem. 282:29658-29666(2007).
RN [8]
RP TISSUE SPECIFICITY, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=27641616; DOI=10.1038/srep33516;
RA Marginedas-Freixa I., Hattab C., Bouyer G., Halle F., Chene A.,
RA Lefevre S.D., Cambot M., Cueff A., Schmitt M., Gamain B., Lacapere J.J.,
RA Egee S., Bihel F., Le Van Kim C., Ostuni M.A.;
RT "TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to
RT the inhibition of P. falciparum growth in human blood.";
RL Sci. Rep. 6:33516-33516(2016).
RN [9]
RP VARIANT GLU-303.
RX PubMed=25787250; DOI=10.1073/pnas.1503696112;
RA Cromer M.K., Choi M., Nelson-Williams C., Fonseca A.L., Kunstman J.W.,
RA Korah R.M., Overton J.D., Mane S., Kenney B., Malchoff C.D., Stalberg P.,
RA Akerstroem G., Westin G., Hellman P., Carling T., Bjoerklund P.,
RA Lifton R.P.;
RT "Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in
RT insulin-producing adenomas.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:4062-4067(2015).
CC -!- FUNCTION: ADP:ATP antiporter that mediates import of ADP into the
CC mitochondrial matrix for ATP synthesis, and export of ATP out to fuel
CC the cell (By similarity). Cycles between the cytoplasmic-open state (c-
CC state) and the matrix-open state (m-state): operates by the alternating
CC access mechanism with a single substrate-binding site intermittently
CC exposed to either the cytosolic (c-state) or matrix (m-state) side of
CC the inner mitochondrial membrane (By similarity). Specifically required
CC during spermatogenesis, probably to mediate ADP:ATP exchange in
CC spermatocytes (PubMed:17137571). Large ATP supplies from mitochondria
CC may be critical for normal progression of spermatogenesis during early
CC stages of meiotic prophase I, including DNA double-strand break repair
CC and chromosomal synapsis (By similarity). In addition to its ADP:ATP
CC antiporter activity, also involved in mitochondrial uncoupling and
CC mitochondrial permeability transition pore (mPTP) activity (By
CC similarity). Plays a role in mitochondrial uncoupling by acting as a
CC proton transporter: proton transport uncouples the proton flows via the
CC electron transport chain and ATP synthase to reduce the efficiency of
CC ATP production and cause mitochondrial thermogenesis (By similarity).
CC Proton transporter activity is inhibited by ADP:ATP antiporter
CC activity, suggesting that SLC25A31/ANT4 acts as a master regulator of
CC mitochondrial energy output by maintaining a delicate balance between
CC ATP production (ADP:ATP antiporter activity) and thermogenesis (proton
CC transporter activity) (By similarity). Proton transporter activity
CC requires free fatty acids as cofactor, but does not transport it (By
CC similarity). Also plays a key role in mPTP opening, a non-specific pore
CC that enables free passage of the mitochondrial membranes to solutes of
CC up to 1.5 kDa, and which contributes to cell death (By similarity). It
CC is however unclear if SLC25A31/ANT4 constitutes a pore-forming
CC component of mPTP or regulates it (By similarity).
CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P48962,
CC ECO:0000250|UniProtKB:Q3V132, ECO:0000269|PubMed:17137571}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ADP(in) + ATP(out) = ADP(out) + ATP(in); Xref=Rhea:RHEA:34999,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000250|UniProtKB:P48962};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378;
CC Evidence={ECO:0000250|UniProtKB:P48962};
CC -!- ACTIVITY REGULATION: The matrix-open state (m-state) is inhibited by
CC the membrane-permeable bongkrekic acid (BKA). The cytoplasmic-open
CC state (c-state) is inhibited by the membrane-impermeable toxic
CC inhibitor carboxyatractyloside (CATR) (By similarity). Proton
CC transporter activity is inhibited by ADP:ATP antiporter activity (By
CC similarity). {ECO:0000250|UniProtKB:G2QNH0,
CC ECO:0000250|UniProtKB:P48962}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:G2QNH0,
CC ECO:0000250|UniProtKB:P02722}.
CC -!- INTERACTION:
CC Q9H0C2; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-6149672, EBI-10171774;
CC Q9H0C2; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-6149672, EBI-16439278;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:P02722}; Multi-pass membrane protein
CC {ECO:0000255}. Membrane {ECO:0000269|PubMed:27641616}; Multi-pass
CC membrane protein {ECO:0000255}. Cell projection, cilium, flagellum
CC membrane {ECO:0000269|PubMed:17137571}; Multi-pass membrane protein
CC {ECO:0000255}. Note=In sperm flagellum this protein is located in the
CC fibrous sheath, a non-mitochondrial region (PubMed:17137571). May
CC localize to non-mitochondrial membranes (PubMed:27641616).
CC {ECO:0000269|PubMed:17137571, ECO:0000269|PubMed:27641616}.
CC -!- TISSUE SPECIFICITY: Expressed in brain, liver, sperm and testis
CC (PubMed:15670820, PubMed:17137571). In testis, expressed at higher
CC level in spermatocytes, while it is expressed at lower level in
CC spermatogonial cells (PubMed:17681941). Expressed in erythrocytes (at
CC protein level) (PubMed:27641616). {ECO:0000269|PubMed:15670820,
CC ECO:0000269|PubMed:17137571, ECO:0000269|PubMed:17681941,
CC ECO:0000269|PubMed:27641616}.
CC -!- DOMAIN: The transmembrane helices are not perpendicular to the plane of
CC the membrane, but cross the membrane at an angle. Odd-numbered
CC transmembrane helices exhibit a sharp kink, due to the presence of a
CC conserved proline residue. {ECO:0000250|UniProtKB:P02722}.
CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family.
CC {ECO:0000305}.
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DR EMBL; AJ863129; CAI05952.1; -; mRNA.
DR EMBL; AY550240; AAT42263.1; -; mRNA.
DR EMBL; AL136857; CAB66791.1; -; mRNA.
DR EMBL; AC093591; AAY40974.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX05199.1; -; Genomic_DNA.
DR EMBL; BC022032; AAH22032.1; -; mRNA.
DR CCDS; CCDS3733.1; -.
DR RefSeq; NP_001305396.1; NM_001318467.1.
DR RefSeq; NP_112581.1; NM_031291.3.
DR AlphaFoldDB; Q9H0C2; -.
DR SMR; Q9H0C2; -.
DR BioGRID; 123649; 54.
DR IntAct; Q9H0C2; 6.
DR STRING; 9606.ENSP00000281154; -.
DR TCDB; 2.A.29.1.8; the mitochondrial carrier (mc) family.
DR iPTMnet; Q9H0C2; -.
DR PhosphoSitePlus; Q9H0C2; -.
DR SwissPalm; Q9H0C2; -.
DR BioMuta; SLC25A31; -.
DR DMDM; 74752557; -.
DR EPD; Q9H0C2; -.
DR jPOST; Q9H0C2; -.
DR MassIVE; Q9H0C2; -.
DR MaxQB; Q9H0C2; -.
DR PaxDb; Q9H0C2; -.
DR PeptideAtlas; Q9H0C2; -.
DR PRIDE; Q9H0C2; -.
DR ProteomicsDB; 80251; -.
DR Antibodypedia; 3024; 154 antibodies from 24 providers.
DR DNASU; 83447; -.
DR Ensembl; ENST00000281154.6; ENSP00000281154.4; ENSG00000151475.6.
DR GeneID; 83447; -.
DR KEGG; hsa:83447; -.
DR MANE-Select; ENST00000281154.6; ENSP00000281154.4; NM_031291.4; NP_112581.1.
DR UCSC; uc003ifl.4; human.
DR CTD; 83447; -.
DR DisGeNET; 83447; -.
DR GeneCards; SLC25A31; -.
DR HGNC; HGNC:25319; SLC25A31.
DR HPA; ENSG00000151475; Tissue enriched (testis).
DR MIM; 610796; gene.
DR neXtProt; NX_Q9H0C2; -.
DR OpenTargets; ENSG00000151475; -.
DR PharmGKB; PA142670904; -.
DR VEuPathDB; HostDB:ENSG00000151475; -.
DR eggNOG; KOG0749; Eukaryota.
DR GeneTree; ENSGT00940000160648; -.
DR HOGENOM; CLU_015166_12_0_1; -.
DR InParanoid; Q9H0C2; -.
DR OMA; AHCWLVI; -.
DR OrthoDB; 870903at2759; -.
DR PhylomeDB; Q9H0C2; -.
DR TreeFam; TF300743; -.
DR PathwayCommons; Q9H0C2; -.
DR SignaLink; Q9H0C2; -.
DR BioGRID-ORCS; 83447; 21 hits in 1068 CRISPR screens.
DR ChiTaRS; SLC25A31; human.
DR GeneWiki; SLC25A31; -.
DR GenomeRNAi; 83447; -.
DR Pharos; Q9H0C2; Tbio.
DR PRO; PR:Q9H0C2; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9H0C2; protein.
DR Bgee; ENSG00000151475; Expressed in adult organism and 16 other tissues.
DR Genevisible; Q9H0C2; HS.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR GO; GO:0005757; C:mitochondrial permeability transition pore complex; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:LIFEdb.
DR GO; GO:0031514; C:motile cilium; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-KW.
DR GO; GO:0005471; F:ATP:ADP antiporter activity; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0007141; P:male meiosis I; ISS:UniProtKB.
DR GO; GO:0140021; P:mitochondrial ADP transmembrane transport; IEA:InterPro.
DR GO; GO:1990544; P:mitochondrial ATP transmembrane transport; IBA:GO_Central.
DR GO; GO:1901029; P:negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IBA:GO_Central.
DR GO; GO:0046902; P:regulation of mitochondrial membrane permeability; ISS:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR Gene3D; 1.50.40.10; -; 1.
DR InterPro; IPR002113; ADT_euk_type.
DR InterPro; IPR002067; Mit_carrier.
DR InterPro; IPR018108; Mitochondrial_sb/sol_carrier.
DR InterPro; IPR023395; Mt_carrier_dom_sf.
DR PANTHER; PTHR45635; PTHR45635; 1.
DR Pfam; PF00153; Mito_carr; 3.
DR PRINTS; PR00927; ADPTRNSLCASE.
DR PRINTS; PR00926; MITOCARRIER.
DR SUPFAM; SSF103506; SSF103506; 1.
DR PROSITE; PS50920; SOLCAR; 3.
PE 1: Evidence at protein level;
KW Antiport; Cell membrane; Cell projection; Cilium; Differentiation;
KW Flagellum; Membrane; Mitochondrion; Mitochondrion inner membrane;
KW Reference proteome; Repeat; Spermatogenesis; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..315
FT /note="ADP/ATP translocase 4"
FT /id="PRO_0000297624"
FT TOPO_DOM 1..19
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT TRANSMEM 20..49
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT TOPO_DOM 50..86
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305"
FT TRANSMEM 87..111
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT TOPO_DOM 112..121
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT TRANSMEM 122..142
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT TOPO_DOM 143..190
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305"
FT TRANSMEM 191..211
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT TOPO_DOM 212..222
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT TRANSMEM 223..243
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT TOPO_DOM 244..283
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305"
FT TRANSMEM 284..301
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT TOPO_DOM 302..315
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT REPEAT 18..110
FT /note="Solcar 1"
FT REPEAT 123..213
FT /note="Solcar 2"
FT REPEAT 220..307
FT /note="Solcar 3"
FT REGION 247..252
FT /note="Important for transport activity"
FT /evidence="ECO:0000250|UniProtKB:P12235"
FT MOTIF 247..252
FT /note="Nucleotide carrier signature motif"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT BINDING 92
FT /ligand="ADP"
FT /ligand_id="ChEBI:CHEBI:456216"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT BINDING 104
FT /ligand="ADP"
FT /ligand_id="ChEBI:CHEBI:456216"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT BINDING 247
FT /ligand="ADP"
FT /ligand_id="ChEBI:CHEBI:456216"
FT /evidence="ECO:0000250|UniProtKB:P02722"
FT VARIANT 303
FT /note="K -> E"
FT /evidence="ECO:0000269|PubMed:25787250"
FT /id="VAR_074177"
SQ SEQUENCE 315 AA; 35022 MW; 9ACE26062CCC9675 CRC64;
MHREPAKKKA EKRLFDASSF GKDLLAGGVA AAVSKTAVAP IERVKLLLQV QASSKQISPE
ARYKGMVDCL VRIPREQGFF SFWRGNLANV IRYFPTQALN FAFKDKYKQL FMSGVNKEKQ
FWRWFLANLA SGGAAGATSL CVVYPLDFAR TRLGVDIGKG PEERQFKGLG DCIMKIAKSD
GIAGLYQGFG VSVQGIIVYR ASYFGAYDTV KGLLPKPKKT PFLVSFFIAQ VVTTCSGILS
YPFDTVRRRM MMQSGEAKRQ YKGTLDCFVK IYQHEGISSF FRGAFSNVLR GTGGALVLVL
YDKIKEFFHI DIGGR
