LETM1_HUMAN
ID LETM1_HUMAN Reviewed; 739 AA.
AC O95202; B4DED2; Q9UF65;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Mitochondrial proton/calcium exchanger protein {ECO:0000305};
DE AltName: Full=Leucine zipper-EF-hand-containing transmembrane protein 1;
DE Flags: Precursor;
GN Name=LETM1 {ECO:0000312|HGNC:HGNC:6556};
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).
RX PubMed=10486213; DOI=10.1006/geno.1999.5881;
RA Endele S., Fuhry M., Pak S.-J., Zabel B.U., Winterpacht A.;
RT "LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein,
RT flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in
RT most WHS patients.";
RL Genomics 60:218-225(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Cerebellum, and Thymus;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Skin;
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 [5]
RP SUBCELLULAR LOCATION.
RX PubMed=14706454; DOI=10.1016/j.ygeno.2003.08.013;
RA Schlickum S., Moghekar A., Simpson J.C., Steglich C., O'Brien R.J.,
RA Winterpacht A., Endele S.U.;
RT "LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an
RT evolutionarily conserved mitochondrial protein.";
RL Genomics 83:254-261(2004).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=15138253; DOI=10.1074/jbc.m403607200;
RA Nowikovsky K., Froschauer E.M., Zsurka G., Samaj J., Reipert S.,
RA Kolisek M., Wiesenberger G., Schweyen R.J.;
RT "The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+
RT homeostasis with a potential role in the Wolf-Hirschhorn syndrome.";
RL J. Biol. Chem. 279:30307-30315(2004).
RN [7]
RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND INTERACTION WITH BCS1L.
RX PubMed=18628306; DOI=10.1242/jcs.026625;
RA Tamai S., Iida H., Yokota S., Sayano T., Kiguchiya S., Ishihara N.,
RA Hayashi J., Mihara K., Oka T.;
RT "Characterization of the mitochondrial protein LETM1, which maintains the
RT mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L.";
RL J. Cell Sci. 121:2588-2600(2008).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-597, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
RP FUNCTION, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=19797662; DOI=10.1126/science.1175145;
RA Jiang D., Zhao L., Clapham D.E.;
RT "Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+
RT antiporter.";
RL Science 326:144-147(2009).
RN [10]
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 [11]
RP FUNCTION.
RX PubMed=24898248; DOI=10.1074/jbc.m113.540898;
RA De Marchi U., Santo-Domingo J., Castelbou C., Sekler I., Wiederkehr A.,
RA Demaurex N.;
RT "NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion,
RT thereby limiting Ca2+-induced NAD(P)H production and modulating matrix
RT redox state.";
RL J. Biol. Chem. 289:20377-20385(2014).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [13]
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).
CC -!- FUNCTION: Mitochondrial proton/calcium antiporter that mediates proton-
CC dependent calcium efflux from mitochondrion (PubMed:19797662). Crucial
CC for the maintenance of mitochondrial tubular networks and for the
CC assembly of the supercomplexes of the respiratory chain
CC (PubMed:18628306). Required for the maintenance of the tubular shape
CC and cristae organization (PubMed:18628306). In contrast to SLC8B1/NCLX,
CC does not constitute the major factor for mitochondrial calcium
CC extrusion (PubMed:24898248). {ECO:0000269|PubMed:18628306,
CC ECO:0000269|PubMed:19797662, ECO:0000269|PubMed:24898248}.
CC -!- ACTIVITY REGULATION: Inhibited by ruthenium red or its derivative
CC Ru360. {ECO:0000269|PubMed:19797662}.
CC -!- SUBUNIT: Homohexamer (By similarity). Can form 2 complexes: a major
CC (300 kDa) and a minor complex (500-600 kDa) (PubMed:18628306).
CC Interacts with BCS1L (PubMed:18628306). {ECO:0000250|UniProtKB:Q9Z2I0,
CC ECO:0000269|PubMed:18628306}.
CC -!- INTERACTION:
CC O95202; Q3LI66: KRTAP6-2; NbExp=3; IntAct=EBI-1052895, EBI-11962084;
CC O95202; P25788: PSMA3; NbExp=3; IntAct=EBI-1052895, EBI-348380;
CC O95202; P36508: ZNF76; NbExp=3; IntAct=EBI-1052895, EBI-7254550;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:14706454, ECO:0000269|PubMed:15138253,
CC ECO:0000269|PubMed:18628306, ECO:0000269|PubMed:19797662}; Single-pass
CC membrane protein {ECO:0000269|PubMed:14706454,
CC ECO:0000269|PubMed:15138253, ECO:0000269|PubMed:18628306}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O95202-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O95202-2; Sequence=VSP_037814, VSP_037815, VSP_037816;
CC Name=3;
CC IsoId=O95202-3; Sequence=VSP_037815, VSP_037816;
CC -!- MISCELLANEOUS: [Isoform 2]: May be due to intron retention.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: May be due to intron retention.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the LETM1 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB63769.2; Type=Erroneous translation; Note=Incomplete prediction of CDS at the C-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF061025; AAD13138.1; -; mRNA.
DR EMBL; AK293572; BAG57043.1; -; mRNA.
DR EMBL; AK310563; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AL133650; CAB63769.2; ALT_SEQ; mRNA.
DR EMBL; BC014500; AAH14500.1; -; mRNA.
DR EMBL; BC021208; AAH21208.1; -; mRNA.
DR CCDS; CCDS3355.1; -. [O95202-1]
DR PIR; T43494; T43494.
DR RefSeq; NP_036450.1; NM_012318.2. [O95202-1]
DR AlphaFoldDB; O95202; -.
DR SMR; O95202; -.
DR BioGRID; 110145; 230.
DR IntAct; O95202; 50.
DR MINT; O95202; -.
DR STRING; 9606.ENSP00000305653; -.
DR TCDB; 2.A.97.1.1; the mitochondrial inner membrane k(+)/h(+) and ca(2+)/h(+) exchanger (letm1) family.
DR iPTMnet; O95202; -.
DR MetOSite; O95202; -.
DR PhosphoSitePlus; O95202; -.
DR SwissPalm; O95202; -.
DR BioMuta; LETM1; -.
DR EPD; O95202; -.
DR jPOST; O95202; -.
DR MassIVE; O95202; -.
DR MaxQB; O95202; -.
DR PaxDb; O95202; -.
DR PeptideAtlas; O95202; -.
DR PRIDE; O95202; -.
DR ProteomicsDB; 50710; -. [O95202-1]
DR ProteomicsDB; 50711; -. [O95202-2]
DR ProteomicsDB; 50712; -. [O95202-3]
DR Antibodypedia; 2597; 266 antibodies from 30 providers.
DR DNASU; 3954; -.
DR Ensembl; ENST00000302787.3; ENSP00000305653.2; ENSG00000168924.15. [O95202-1]
DR GeneID; 3954; -.
DR KEGG; hsa:3954; -.
DR MANE-Select; ENST00000302787.3; ENSP00000305653.2; NM_012318.3; NP_036450.1.
DR UCSC; uc003gdv.3; human. [O95202-1]
DR CTD; 3954; -.
DR DisGeNET; 3954; -.
DR GeneCards; LETM1; -.
DR HGNC; HGNC:6556; LETM1.
DR HPA; ENSG00000168924; Low tissue specificity.
DR MalaCards; LETM1; -.
DR MIM; 604407; gene.
DR neXtProt; NX_O95202; -.
DR OpenTargets; ENSG00000168924; -.
DR Orphanet; 280; Wolf-Hirschhorn syndrome.
DR PharmGKB; PA30335; -.
DR VEuPathDB; HostDB:ENSG00000168924; -.
DR eggNOG; KOG1043; Eukaryota.
DR GeneTree; ENSGT00950000183167; -.
DR HOGENOM; CLU_008958_2_1_1; -.
DR InParanoid; O95202; -.
DR OMA; EILHYYH; -.
DR OrthoDB; 516860at2759; -.
DR PhylomeDB; O95202; -.
DR TreeFam; TF316321; -.
DR PathwayCommons; O95202; -.
DR Reactome; R-HSA-8949215; Mitochondrial calcium ion transport.
DR Reactome; R-HSA-9013408; RHOG GTPase cycle.
DR SignaLink; O95202; -.
DR SIGNOR; O95202; -.
DR BioGRID-ORCS; 3954; 642 hits in 1084 CRISPR screens.
DR ChiTaRS; LETM1; human.
DR GeneWiki; LETM1; -.
DR GenomeRNAi; 3954; -.
DR Pharos; O95202; Tbio.
DR PRO; PR:O95202; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; O95202; protein.
DR Bgee; ENSG00000168924; Expressed in mucosa of transverse colon and 180 other tissues.
DR Genevisible; O95202; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005509; F:calcium ion binding; TAS:UniProtKB.
DR GO; GO:0015369; F:calcium:proton antiporter activity; IDA:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; IEA:InterPro.
DR GO; GO:0099093; P:calcium export from the mitochondrion; IDA:UniProtKB.
DR GO; GO:0006875; P:cellular metal ion homeostasis; IBA:GO_Central.
DR GO; GO:0042407; P:cristae formation; IMP:UniProtKB.
DR GO; GO:0051560; P:mitochondrial calcium ion homeostasis; IDA:UniProtKB.
DR GO; GO:0006851; P:mitochondrial calcium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0051562; P:negative regulation of mitochondrial calcium ion concentration; IMP:UniProtKB.
DR GO; GO:0034214; P:protein hexamerization; ISS:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; ISS:UniProtKB.
DR GO; GO:1900069; P:regulation of cellular hyperosmotic salinity response; IMP:UniProtKB.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR011685; LETM1-like.
DR InterPro; IPR044202; LETM1/MDM38-like.
DR InterPro; IPR033122; LETM1_RBD.
DR PANTHER; PTHR14009; PTHR14009; 1.
DR Pfam; PF07766; LETM1; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
DR PROSITE; PS51758; LETM1_RBD; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Antiport; Calcium; Calcium transport;
KW Coiled coil; Ion transport; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion inner membrane; Reference proteome; Transit peptide;
KW Transmembrane; Transmembrane helix; Transport.
FT TRANSIT 1..115
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 116..739
FT /note="Mitochondrial proton/calcium exchanger protein"
FT /id="PRO_0000017694"
FT TOPO_DOM 116..208
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2I0"
FT TRANSMEM 209..229
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 230..739
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2I0"
FT DOMAIN 252..537
FT /note="Letm1 RBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01094"
FT DOMAIN 663..698
FT /note="EF-hand"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT REGION 718..739
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 115..136
FT /evidence="ECO:0000255"
FT COILED 462..490
FT /evidence="ECO:0000255"
FT COILED 537..627
FT /evidence="ECO:0000255"
FT COILED 708..739
FT /evidence="ECO:0000255"
FT BINDING 676
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 678
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 680
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 682
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 687
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT MOD_RES 597
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 1..48
FT /note="MASILLRSCRGRAPARLPPPPRYTVPRGSPGDPAHLSCASTLGLRNCL ->
FT MRHTWPFR (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:17974005"
FT /id="VSP_037814"
FT VAR_SEQ 292..294
FT /note="KIR -> QVL (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:17974005"
FT /id="VSP_037815"
FT VAR_SEQ 295..739
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:17974005"
FT /id="VSP_037816"
SQ SEQUENCE 739 AA; 83354 MW; 942E9138F299D94F CRC64;
MASILLRSCR GRAPARLPPP PRYTVPRGSP GDPAHLSCAS TLGLRNCLNV PFGCCTPIHP
VYTSSRGDHL GCWALRPECL RIVSRAPWTS TSVGFVAVGP QCLPVRGWHS SRPVRDDSVV
EKSLKSLKDK NKKLEEGGPV YSPPAEVVVK KSLGQRVLDE LKHYYHGFRL LWIDTKIAAR
MLWRILNGHS LTRRERRQFL RICADLFRLV PFLVFVVVPF MEFLLPVAVK LFPNMLPSTF
ETQSLKEERL KKELRVKLEL AKFLQDTIEE MALKNKAAKG SATKDFSVFF QKIRETGERP
SNEEIMRFSK LFEDELTLDN LTRPQLVALC KLLELQSIGT NNFLRFQLTM RLRSIKADDK
LIAEEGVDSL NVKELQAACR ARGMRALGVT EDRLRGQLKQ WLDLHLHQEI PTSLLILSRA
MYLPDTLSPA DQLKSTLQTL PEIVAKEAQV KVAEVEGEQV DNKAKLEATL QEEAAIQQEH
REKELQKRSE VAKDFEPERV VAAPQRPGTE PQPEMPDTVL QSETLKDTAP VLEGLKEEEI
TKEEIDILSD ACSKLQEQKK SLTKEKEELE LLKEDVQDYS EDLQEIKKEL SKTGEEKYVE
ESKASKRLTK RVQQMIGQID GLISQLEMDQ QAGKLAPANG MPTGENVISV AELINAMKQV
KHIPESKLTS LAAALDENKD GKVNIDDLVK VIELVDKEDV HISTSQVAEI VATLEKEEKV
EEKEKAKEKA EKEVAEVKS