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   27-MAR-2024, entry version 192.
DE   RecName: Full=Mitochondrial proton/calcium exchanger protein {ECO:0000305};
DE   AltName: Full=Electroneutral mitochondrial K(+)/H(+)exchanger {ECO:0000303|PubMed:36055214};
DE            Short=KHE {ECO:0000303|PubMed:36055214};
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, SUBCELLULAR LOCATION, AND TRANSPORTER
RP   ACTIVITY.
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, AND TRANSPORTER ACTIVITY.
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   FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP   REGULATION.
RX   PubMed=24344246; DOI=10.1085/jgp.201311096;
RA   Tsai M.F., Jiang D., Zhao L., Clapham D., Miller C.;
RT   "Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1.";
RL   J. Gen. Physiol. 143:67-73(2014).
RN   [13]
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   [14]
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   [15]
RP   FUNCTION, TRANSPORTER ACTIVITY, PHOSPHORYLATION AT THR-192, AND MUTAGENESIS
RP   OF THR-192.
RX   PubMed=29123128; DOI=10.1038/s41467-017-01435-1;
RA   Huang E., Qu D., Huang T., Rizzi N., Boonying W., Krolak D., Ciana P.,
RA   Woulfe J., Klein C., Slack R.S., Figeys D., Park D.S.;
RT   "PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium
RT   transport and protects neurons against mitochondrial stress.";
RL   Nat. Commun. 8:1399-1399(2017).
RN   [16]
RP   FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY, AND MUTAGENESIS OF ASP-359;
RP   ARG-382; GLY-383 AND MET-384.
RX   PubMed=32139798; DOI=10.1038/s42003-020-0832-5;
RA   Nakamura S., Matsui A., Akabane S., Tamura Y., Hatano A., Miyano Y.,
RA   Omote H., Kajikawa M., Maenaka K., Moriyama Y., Endo T., Oka T.;
RT   "The mitochondrial inner membrane protein LETM1 modulates cristae
RT   organization through its LETM domain.";
RL   Commun. Biol. 3:99-99(2020).
RN   [17]
RP   FUNCTION, TRANSPORTER ACTIVITY, AND INTERACTION WITH GHITM.
RX   PubMed=36321428; DOI=10.15252/embr.202254978;
RA   Austin S., Mekis R., Mohammed S.E.M., Scalise M., Wang W.A., Galluccio M.,
RA   Pfeiffer C., Borovec T., Parapatics K., Vitko D., Dinhopl N., Demaurex N.,
RA   Bennett K.L., Indiveri C., Nowikovsky K.;
RT   "TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.";
RL   EMBO Rep. 23:e54978-e54978(2022).
RN   [18]
RP   VARIANTS CONDMIM LYS-252 DEL; ASN-293; GLN-294; SER-300; ASN-358; PRO-380;
RP   HIS-393 AND ARG-587, CHARACTERIZATION OF VARIANTS CONDMIM LYS-252 DEL;
RP   ASN-293; GLN-294; SER-300; ASN-358; PRO-380 AND ARG-587, VARIANT LEU-305,
RP   CHARACTERIZATION OF VARIANT LEU-305, INVOLVEMENT IN CONDMIM, FUNCTION, AND
RP   TRANSPORTER ACTIVITY.
RX   PubMed=36055214; DOI=10.1016/j.ajhg.2022.07.007;
RA   Kaiyrzhanov R., Mohammed S.E.M., Maroofian R., Husain R.A., Catania A.,
RA   Torraco A., Alahmad A., Dutra-Clarke M., Groenborg S., Sudarsanam A.,
RA   Vogt J., Arrigoni F., Baptista J., Haider S., Feichtinger R.G.,
RA   Bernardi P., Zulian A., Gusic M., Efthymiou S., Bai R., Bibi F., Horga A.,
RA   Martinez-Agosto J.A., Lam A., Manole A., Rodriguez D.P., Durigon R.,
RA   Pyle A., Albash B., Dionisi-Vici C., Murphy D., Martinelli D.,
RA   Bugiardini E., Allis K., Lamperti C., Reipert S., Risom L., Laugwitz L.,
RA   Di Nottia M., McFarland R., Vilarinho L., Hanna M., Prokisch H., Mayr J.A.,
RA   Bertini E.S., Ghezzi D., Oestergaard E., Wortmann S.B., Carrozzo R.,
RA   Haack T.B., Taylor R.W., Spinazzola A., Nowikovsky K., Houlden H.;
RT   "Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to
RT   a clinical spectrum with predominant nervous system involvement.";
RL   Am. J. Hum. Genet. 109:1692-1712(2022).
CC   -!- FUNCTION: Plays an important role in maintenance of mitochondrial
CC       morphology and in mediating either calcium or potassium/proton antiport
CC       (PubMed:18628306, PubMed:19797662, PubMed:24898248, PubMed:24344246,
CC       PubMed:29123128, PubMed:32139798, PubMed:36321428, PubMed:36055214).
CC       Mediates proton-dependent calcium efflux from mitochondrion
CC       (PubMed:19797662, PubMed:24344246, PubMed:29123128). Functions also as
CC       an electroneutral mitochondrial proton/potassium exchanger
CC       (PubMed:24898248, PubMed:36055214, PubMed:36321428). Crucial for the
CC       maintenance of mitochondrial tubular networks and for the assembly of
CC       the supercomplexes of the respiratory chain (PubMed:18628306,
CC       PubMed:36055214). Required for the maintenance of the tubular shape and
CC       cristae organization (PubMed:18628306, PubMed:32139798).
CC       {ECO:0000269|PubMed:18628306, ECO:0000269|PubMed:19797662,
CC       ECO:0000269|PubMed:24344246, ECO:0000269|PubMed:24898248,
CC       ECO:0000269|PubMed:29123128, ECO:0000269|PubMed:32139798,
CC       ECO:0000269|PubMed:36055214, ECO:0000269|PubMed:36321428}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Ca(2+)(in) + 2 H(+)(out) = Ca(2+)(out) + 2 H(+)(in);
CC         Xref=Rhea:RHEA:72199, ChEBI:CHEBI:15378, ChEBI:CHEBI:29108;
CC         Evidence={ECO:0000269|PubMed:19797662, ECO:0000269|PubMed:24344246,
CC         ECO:0000269|PubMed:29123128};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H(+)(out) + K(+)(in) = H(+)(in) + K(+)(out);
CC         Xref=Rhea:RHEA:29467, ChEBI:CHEBI:15378, ChEBI:CHEBI:29103;
CC         Evidence={ECO:0000269|PubMed:24898248, ECO:0000269|PubMed:36055214,
CC         ECO:0000269|PubMed:36321428};
CC   -!- ACTIVITY REGULATION: Inhibited by ruthenium red or its derivative
CC       Ru360. {ECO:0000269|PubMed:19797662, ECO:0000269|PubMed:24344246}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=27 uM for calcium transport {ECO:0000269|PubMed:24344246};
CC         Vmax=21 pmol/sec/ug enzyme for calcium transport
CC         {ECO:0000269|PubMed:24344246};
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). Interacts with GHITM
CC       (PubMed:36321428). {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,
CC       ECO:0000269|PubMed:32139798}; Single-pass membrane protein
CC       {ECO:0000255}.
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   -!- PTM: PINK1-mediated phosphorylation at Thr-192, positively regulates
CC       its mitochondrial calcium transport activity.
CC       {ECO:0000269|PubMed:29123128}.
CC   -!- DISEASE: Neurodegeneration, childhood-onset, with multisystem
CC       involvement due to mitochondrial dysfunction (CONDMIM) [MIM:620089]: An
CC       autosomal recessive disorder characterized primarily by global
CC       developmental delay and variably impaired intellectual development with
CC       speech delay apparent from infancy. Affected individuals have
CC       hypotonia, poor feeding, poor overall growth, and respiratory distress
CC       early in life. Other features include visual impairment due to optic
CC       atrophy, sensorineural hearing loss, and neuromuscular abnormalities.
CC       Features suggestive of a mitochondrial disorder include cataracts,
CC       cardiomyopathy, diabetes mellitus, combined oxidative phosphorylation
CC       deficiency, and increased lactate. Some patients develop seizures, some
CC       have dysmorphic facial features, and some have non-specific
CC       abnormalities on brain imaging. Death in childhood may occur.
CC       {ECO:0000269|PubMed:36055214}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
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   -!- CAUTION: There are conflicting results concerning the role of LETM1 as
CC       a mitochondrial proton/calcium exchanger. According to
CC       (PubMed:19797662, PubMed:24344246, PubMed:29123128) LETM1 has been
CC       shown to function as a proton/calcium exchanger. However
CC       (PubMed:36321428) demonstrates the absence of this function in LETM1.
CC       {ECO:0000269|PubMed:19797662, ECO:0000269|PubMed:24344246,
CC       ECO:0000269|PubMed:29123128, ECO:0000269|PubMed:36321428}.
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; 249.
DR   IntAct; O95202; 54.
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   GlyGen; O95202; 1 site, 1 O-linked glycan (1 site).
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; 9606-ENSP00000305653; -.
DR   PeptideAtlas; O95202; -.
DR   ProteomicsDB; 50710; -. [O95202-1]
DR   ProteomicsDB; 50711; -. [O95202-2]
DR   ProteomicsDB; 50712; -. [O95202-3]
DR   Pumba; O95202; -.
DR   Antibodypedia; 2597; 291 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   AGR; HGNC:6556; -.
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   MIM; 620089; phenotype.
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; HGFRHLH; -.
DR   OrthoDB; 375855at2759; -.
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; 671 hits in 1163 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 182 other cell types or tissues.
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:0006816; P:calcium ion transport; IMP:UniProtKB.
DR   GO; GO:0042407; P:cristae formation; IMP:UniProtKB.
DR   GO; GO:0007007; P:inner mitochondrial membrane organization; 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:0140141; P:mitochondrial potassium ion transmembrane transport; IMP: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   Gene3D; 1.10.238.10; EF-hand; 1.
DR   InterPro; IPR011992; EF-hand-dom_pair.
DR   InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR   InterPro; IPR002048; EF_hand_dom.
DR   InterPro; IPR033122; LETM1-like_RBD.
DR   InterPro; IPR044202; LETM1/MDM38-like.
DR   PANTHER; PTHR14009; LEUCINE ZIPPER-EF-HAND CONTAINING TRANSMEMBRANE PROTEIN; 1.
DR   PANTHER; PTHR14009:SF8; MITOCHONDRIAL PROTON_CALCIUM EXCHANGER PROTEIN; 1.
DR   Pfam; PF07766; LETM1_RBD; 1.
DR   SUPFAM; SSF47473; EF-hand; 1.
DR   PROSITE; PS00018; EF_HAND_1; 1.
DR   PROSITE; PS50222; EF_HAND_2; 1.
DR   PROSITE; PS51758; LETM1_RBD; 1.
DR   Genevisible; O95202; HS.
PE   1: Evidence at protein level;
KW   Acetylation; Alternative splicing; Antiport; Calcium; Calcium transport;
KW   Coiled coil; Disease variant; Ion transport; Membrane; Metal-binding;
KW   Mitochondrion; Mitochondrion inner membrane; Neurodegeneration;
KW   Phosphoprotein; Potassium; Potassium transport; Reference proteome;
KW   Transit peptide; 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:0000305|PubMed:32139798"
FT   TRANSMEM        209..229
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        230..739
FT                   /note="Mitochondrial matrix"
FT                   /evidence="ECO:0000305|PubMed:32139798"
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         192
FT                   /note="Phosphothreonine; by PINK1"
FT                   /evidence="ECO:0000269|PubMed:29123128"
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"
FT   VARIANT         252
FT                   /note="Missing (in CONDMIM; decreased function in
FT                   mitochondrial potassium ion transmembrane transport; does
FT                   not fully rescue defective proton/potassium exchange in
FT                   letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087731"
FT   VARIANT         293
FT                   /note="I -> N (in CONDMIM; decreased function in
FT                   mitochondrial potassium ion transmembrane transport; does
FT                   not fully rescue defective proton/potassium exchange in
FT                   letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087732"
FT   VARIANT         294
FT                   /note="R -> Q (in CONDMIM; decreased function in
FT                   mitochondrial potassium ion transmembrane transport; does
FT                   not fully rescue defective proton/potassium exchange in
FT                   letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087733"
FT   VARIANT         300
FT                   /note="P -> S (in CONDMIM; homozygous patient cells show
FT                   altered levels of components of the oxidative
FT                   phosphorylation machinery; decreased function in
FT                   mitochondrial potassium ion transmembrane transport; does
FT                   not fully rescue defective proton/potassium exchange in
FT                   letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087734"
FT   VARIANT         305
FT                   /note="I -> L (no effect on mitochondrial potassium ion
FT                   transmembrane transport; it fully rescues defective
FT                   proton/potassium exchange in letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087735"
FT   VARIANT         358
FT                   /note="D -> N (in CONDMIM; homozygous patient cells show
FT                   abnormal mitochondrial morphology and altered levels of
FT                   components of the oxidative phosphorylation machinery; loss
FT                   of function in mitochondrial potassium ion transmembrane
FT                   transport; does not rescue defective proton/potassium
FT                   exchange in letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087736"
FT   VARIANT         380
FT                   /note="R -> P (in CONDMIM; uncertain significance;
FT                   decreased function in mitochondrial potassium ion
FT                   transmembrane transport; does not fully rescue defective
FT                   proton/potassium exchange in letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087737"
FT   VARIANT         393
FT                   /note="R -> H (in CONDMIM; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087738"
FT   VARIANT         587
FT                   /note="K -> R (in CONDMIM; benign; no effect on
FT                   mitochondrial potassium ion transmembrane transport; it
FT                   fully rescues defective proton/potassium exchange in
FT                   letm1-deficient yeast)"
FT                   /evidence="ECO:0000269|PubMed:36055214"
FT                   /id="VAR_087739"
FT   MUTAGEN         192
FT                   /note="T->A: Loss of phosphorylation by PINK1."
FT                   /evidence="ECO:0000269|PubMed:29123128"
FT   MUTAGEN         192
FT                   /note="T->E: Phosphomimetic mutant. Increased rate of
FT                   calcium export from mitochondria."
FT                   /evidence="ECO:0000269|PubMed:29123128"
FT   MUTAGEN         359
FT                   /note="D->A: Loss of ability to complement morphologic
FT                   defects of mitochondria in letm1-deficient yeast mutant.
FT                   Slightly supports growth of letm1-deficient yeast mutant on
FT                   minimal essential medium."
FT                   /evidence="ECO:0000269|PubMed:32139798"
FT   MUTAGEN         382
FT                   /note="R->A: Loss of ability to complement growth defects
FT                   and morphologic defects of mitochondria in letm1-deficient
FT                   yeast mutant; when associated with A-383 and A-384."
FT                   /evidence="ECO:0000269|PubMed:32139798"
FT   MUTAGEN         383
FT                   /note="G->A: Loss of ability to complement growth defects
FT                   and morphologic defects of mitochondria in letm1-deficient
FT                   yeast mutant; when associated with A-382 and A-384."
FT                   /evidence="ECO:0000269|PubMed:32139798"
FT   MUTAGEN         384
FT                   /note="M->A: Loss of ability to complement growth defects
FT                   and morphologic defects of mitochondria in letm1-deficient
FT                   yeast mutant; when associated with A-382 and A-383."
FT                   /evidence="ECO:0000269|PubMed:32139798"
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
//