ID COX15_HUMAN Reviewed; 410 AA. AC Q7KZN9; A8K6I9; O60556; O75878; Q5TD00; Q5TD01; Q7Z3Q3; Q9NTN0; DT 16-AUG-2004, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 27-MAR-2024, entry version 173. DE RecName: Full=Heme A synthase COX15; DE Short=HAS; DE EC=1.17.99.9 {ECO:0000250|UniProtKB:P40086}; DE AltName: Full=Cytochrome c oxidase assembly protein COX15 homolog; GN Name=COX15; 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] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION, AND RP TISSUE SPECIFICITY. RX PubMed=9878253; DOI=10.1006/geno.1998.5580; RA Petruzzella V., Tiranti V., Fernandez P., Ianna P., Carrozzo R., RA Zeviani M.; RT "Identification and characterization of human cDNAs specific to BCS1, RT PET112, SCO1, COX15, and COX11, five genes involved in the formation and RT function of the mitochondrial respiratory chain."; RL Genomics 54:494-504(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND VARIANT MC4DN6 RP TRP-217. RX PubMed=12474143; DOI=10.1086/345489; RA Antonicka H., Mattman A., Carlson C.G., Glerum D.M., Hoffbuhr K.C., RA Leary S.C., Kennaway N.G., Shoubridge E.A.; RT "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic RT pathway, causing early-onset fatal hypertrophic cardiomyopathy."; RL Am. J. Hum. Genet. 72:101-114(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Endometrial tumor; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Muscle, 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 [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 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 [11] RP VARIANT MC4DN6 TRP-217. RX PubMed=15235026; DOI=10.1136/jmg.2003.017426; RA Oquendo C.E., Antonicka H., Shoubridge E.A., Reardon W., Brown G.K.; RT "Functional and genetic studies demonstrate that mutation in the COX15 gene RT can cause Leigh syndrome."; RL J. Med. Genet. 41:540-544(2004). RN [12] RP VARIANT MC4DN6 PRO-344. RX PubMed=15863660; DOI=10.1136/jmg.2004.029926; RA Bugiani M., Tiranti V., Farina L., Uziel G., Zeviani M.; RT "Novel mutations in COX15 in a long surviving Leigh syndrome patient with RT cytochrome c oxidase deficiency."; RL J. Med. Genet. 42:E28-E28(2005). RN [13] RP VARIANT MC4DN6 TRP-217. RX PubMed=21412973; DOI=10.1002/ajmg.a.33881; RA Alfadhel M., Lillquist Y.P., Waters P.J., Sinclair G., Struys E., RA McFadden D., Hendson G., Hyams L., Shoffner J., Vallance H.D.; RT "Infantile cardioencephalopathy due to a COX15 gene defect: report and RT review."; RL Am. J. Med. Genet. A 155:840-844(2011). CC -!- FUNCTION: Catalyzes the second reaction in the biosynthesis of heme A, CC a prosthetic group of mitochondrial cytochrome c oxidase (CcO) CC (PubMed:12474143). Heme A is synthesized from heme B by two sequential CC enzymatic reactions catalyzed by heme O synthase (HOS) and heme A CC synthase (HAS). HAS catalyzes the conversion of heme O to heme A by two CC successive hydroxylations of the methyl group at C8, in a reaction that CC involves matrix ferredoxin and ferredoxin reductase. The first CC hydroxylation forms heme I, the second hydroxylation results in an CC unstable dihydroxymethyl group, which spontaneously dehydrates, CC resulting in the formyl group of heme A (By similarity). CC {ECO:0000250|UniProtKB:P40086, ECO:0000269|PubMed:12474143}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2 A + Fe(II)-heme o + H2O = 2 AH2 + Fe(II)-heme a; CC Xref=Rhea:RHEA:63388, ChEBI:CHEBI:13193, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:17499, ChEBI:CHEBI:60530, ChEBI:CHEBI:61715; CC EC=1.17.99.9; Evidence={ECO:0000250|UniProtKB:P12946}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63389; CC Evidence={ECO:0000250|UniProtKB:P12946}; CC -!- COFACTOR: CC Name=heme b; Xref=ChEBI:CHEBI:60344; CC Evidence={ECO:0000250|UniProtKB:P12946}; CC -!- PATHWAY: Porphyrin-containing compound metabolism; heme A biosynthesis; CC heme A from heme O: step 1/1. {ECO:0000250|UniProtKB:P40086}. CC -!- INTERACTION: CC Q7KZN9; P30041: PRDX6; NbExp=3; IntAct=EBI-3248549, EBI-2255129; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000269|PubMed:9878253}; Multi-pass membrane protein CC {ECO:0000255}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=COX15.1; CC IsoId=Q7KZN9-1; Sequence=Displayed; CC Name=2; Synonyms=COX15.2; CC IsoId=Q7KZN9-2; Sequence=VSP_011281; CC -!- TISSUE SPECIFICITY: Predominantly found in tissues characterized by CC high rates of oxidative phosphorylation (OxPhos), including muscle, CC heart, and brain. {ECO:0000269|PubMed:9878253}. CC -!- DOMAIN: The N-half (TM1-TM4) and C-half (TM5-TM8) domains are connected CC by an intracellular loop. Each domain is formed from four-helix bundles CC and they align in a pseudo twofold symmetry manner. The N-half domain CC is the substrate heme O binding domain and the C-half domain is the CC cofactor heme B binding domain. {ECO:0000250|UniProtKB:P12946}. CC -!- DISEASE: Mitochondrial complex IV deficiency, nuclear type 6 (MC4DN6) CC [MIM:615119]: An autosomal recessive multisystem disorder with variable CC manifestations. Some patients present in the neonatal period with CC encephalomyopathic features, whereas others present later in the first CC year of life with developmental regression. Clinical features include CC microcephaly, encephalopathy, hypertrophic cardiomyopathy, persistent CC lactic acidosis, respiratory distress, hypotonia and seizures. Serum CC lactate is increased, and laboratory studies show decreased CC mitochondrial complex IV protein and activity levels. CC {ECO:0000269|PubMed:12474143, ECO:0000269|PubMed:15235026, CC ECO:0000269|PubMed:15863660, ECO:0000269|PubMed:21412973}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the COX15/CtaA family. Type 2 subfamily. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF026850; AAD08639.1; -; mRNA. DR EMBL; AF044323; AAD08646.1; -; mRNA. DR EMBL; BT007129; AAP35793.1; -; mRNA. DR EMBL; AK291654; BAF84343.1; -; mRNA. DR EMBL; BX537557; CAD97781.1; -; mRNA. DR EMBL; AL133353; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471066; EAW49857.1; -; Genomic_DNA. DR EMBL; BC002382; AAH02382.3; -; mRNA. DR EMBL; BC013403; AAH13403.1; -; mRNA. DR EMBL; BC078161; AAH78161.1; -; mRNA. DR CCDS; CCDS7481.1; -. [Q7KZN9-2] DR CCDS; CCDS7482.1; -. [Q7KZN9-1] DR RefSeq; NP_001307903.1; NM_001320974.1. DR RefSeq; NP_001307904.1; NM_001320975.1. DR RefSeq; NP_001307905.1; NM_001320976.1. DR RefSeq; NP_004367.2; NM_004376.6. [Q7KZN9-2] DR RefSeq; NP_510870.1; NM_078470.5. [Q7KZN9-1] DR AlphaFoldDB; Q7KZN9; -. DR SMR; Q7KZN9; -. DR BioGRID; 107747; 388. DR CORUM; Q7KZN9; -. DR IntAct; Q7KZN9; 203. DR MINT; Q7KZN9; -. DR STRING; 9606.ENSP00000016171; -. DR TCDB; 8.A.174.1.1; the cytochrome c oxidase cox15 assembly protein (cox15) family. DR GlyGen; Q7KZN9; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q7KZN9; -. DR PhosphoSitePlus; Q7KZN9; -. DR SwissPalm; Q7KZN9; -. DR BioMuta; COX15; -. DR DMDM; 51315906; -. DR EPD; Q7KZN9; -. DR jPOST; Q7KZN9; -. DR MassIVE; Q7KZN9; -. DR MaxQB; Q7KZN9; -. DR PaxDb; 9606-ENSP00000016171; -. DR PeptideAtlas; Q7KZN9; -. DR ProteomicsDB; 68724; -. [Q7KZN9-1] DR ProteomicsDB; 68725; -. [Q7KZN9-2] DR Pumba; Q7KZN9; -. DR TopDownProteomics; Q7KZN9-1; -. [Q7KZN9-1] DR Antibodypedia; 17500; 197 antibodies from 28 providers. DR DNASU; 1355; -. DR Ensembl; ENST00000016171.6; ENSP00000016171.6; ENSG00000014919.13. [Q7KZN9-1] DR Ensembl; ENST00000370483.9; ENSP00000359514.5; ENSG00000014919.13. [Q7KZN9-2] DR GeneID; 1355; -. DR KEGG; hsa:1355; -. DR MANE-Select; ENST00000016171.6; ENSP00000016171.6; NM_078470.6; NP_510870.1. DR UCSC; uc001kqb.5; human. [Q7KZN9-1] DR AGR; HGNC:2263; -. DR CTD; 1355; -. DR DisGeNET; 1355; -. DR GeneCards; COX15; -. DR HGNC; HGNC:2263; COX15. DR HPA; ENSG00000014919; Low tissue specificity. DR MalaCards; COX15; -. DR MIM; 603646; gene. DR MIM; 615119; phenotype. DR neXtProt; NX_Q7KZN9; -. DR OpenTargets; ENSG00000014919; -. DR Orphanet; 1561; Fatal infantile cytochrome C oxidase deficiency. DR PharmGKB; PA26779; -. DR VEuPathDB; HostDB:ENSG00000014919; -. DR eggNOG; KOG2725; Eukaryota. DR GeneTree; ENSGT00390000002223; -. DR HOGENOM; CLU_017627_0_1_1; -. DR InParanoid; Q7KZN9; -. DR OMA; AFVCYSW; -. DR OrthoDB; 7506at2759; -. DR PhylomeDB; Q7KZN9; -. DR TreeFam; TF105073; -. DR PathwayCommons; Q7KZN9; -. DR Reactome; R-HSA-189451; Heme biosynthesis. DR SignaLink; Q7KZN9; -. DR UniPathway; UPA00269; UER00713. DR BioGRID-ORCS; 1355; 354 hits in 1154 CRISPR screens. DR ChiTaRS; COX15; human. DR GeneWiki; COX15; -. DR GenomeRNAi; 1355; -. DR Pharos; Q7KZN9; Tbio. DR PRO; PR:Q7KZN9; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q7KZN9; Protein. DR Bgee; ENSG00000014919; Expressed in caput epididymis and 213 other cell types or tissues. DR GO; GO:0070069; C:cytochrome complex; IDA:BHF-UCL. DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central. DR GO; GO:0005746; C:mitochondrial respirasome; TAS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0004129; F:cytochrome-c oxidase activity; TAS:UniProtKB. DR GO; GO:0020037; F:heme binding; TAS:ARUK-UCL. DR GO; GO:0060090; F:molecular adaptor activity; IMP:BHF-UCL. DR GO; GO:0016653; F:oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor; IBA:GO_Central. DR GO; GO:0016627; F:oxidoreductase activity, acting on the CH-CH group of donors; TAS:Reactome. DR GO; GO:0045333; P:cellular respiration; TAS:HGNC-UCL. DR GO; GO:0006784; P:heme A biosynthetic process; IGI:HGNC-UCL. DR GO; GO:0006783; P:heme biosynthetic process; TAS:Reactome. DR GO; GO:0006123; P:mitochondrial electron transport, cytochrome c to oxygen; TAS:HGNC-UCL. DR GO; GO:1902600; P:proton transmembrane transport; IMP:BHF-UCL. DR GO; GO:0008535; P:respiratory chain complex IV assembly; IMP:HGNC-UCL. DR GO; GO:0007585; P:respiratory gaseous exchange by respiratory system; TAS:UniProtKB. DR HAMAP; MF_01665; HemeA_synth_type2; 1. DR InterPro; IPR003780; COX15/CtaA_fam. DR InterPro; IPR023754; HemeA_Synthase_type2. DR InterPro; IPR009003; Peptidase_S1_PA. DR PANTHER; PTHR23289; CYTOCHROME C OXIDASE ASSEMBLY PROTEIN COX15; 1. DR PANTHER; PTHR23289:SF2; CYTOCHROME C OXIDASE ASSEMBLY PROTEIN COX15 HOMOLOG; 1. DR Pfam; PF02628; COX15-CtaA; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR Genevisible; Q7KZN9; HS. PE 1: Evidence at protein level; KW Alternative splicing; Disease variant; Heme biosynthesis; Iron; KW Leigh syndrome; Membrane; Metal-binding; Mitochondrion; KW Mitochondrion inner membrane; Oxidoreductase; KW Primary mitochondrial disease; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..410 FT /note="Heme A synthase COX15" FT /id="PRO_0000183931" FT TOPO_DOM 1..67 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 68..88 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 89..153 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 154..171 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 172..183 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 184..204 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 205..226 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 227..247 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 248..268 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 269..289 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 290..323 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 324..344 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 345..356 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 357..377 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 378..381 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P40086" FT TRANSMEM 382..402 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 403..410 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P40086, ECO:0000305" FT BINDING 152 FT /ligand="heme o" FT /ligand_id="ChEBI:CHEBI:24480" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="axial binding residue" FT /evidence="ECO:0000250|UniProtKB:P12946" FT BINDING 226 FT /ligand="heme o" FT /ligand_id="ChEBI:CHEBI:24480" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="axial binding residue" FT /evidence="ECO:0000250|UniProtKB:P12946" FT BINDING 326 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="axial binding residue" FT /evidence="ECO:0000250|UniProtKB:P12946" FT BINDING 387 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="axial binding residue" FT /evidence="ECO:0000250|UniProtKB:P12946" FT VAR_SEQ 368..410 FT /note="VGLGISTLLMYVPTPLAATHQSGSLALLTGALWLMNELRRVPK -> GPVLF FT NFTFKISDLDEGIRNI (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9878253" FT /id="VSP_011281" FT VARIANT 217 FT /note="R -> W (in MC4DN6; dbSNP:rs28939711)" FT /evidence="ECO:0000269|PubMed:12474143, FT ECO:0000269|PubMed:15235026, ECO:0000269|PubMed:21412973" FT /id="VAR_019596" FT VARIANT 344 FT /note="S -> P (in MC4DN6; dbSNP:rs397514662)" FT /evidence="ECO:0000269|PubMed:15863660" FT /id="VAR_033117" FT CONFLICT 28 FT /note="R -> K (in Ref. 1; AAD08639/AAD08646)" FT /evidence="ECO:0000305" FT CONFLICT 93 FT /note="T -> A (in Ref. 3; CAD97781)" FT /evidence="ECO:0000305" FT CONFLICT Q7KZN9-2:374 FT /note="F -> L (in Ref. 1; AAD08646)" FT /evidence="ECO:0000305" SQ SEQUENCE 410 AA; 46030 MW; 98E9FD9D1D28EFC0 CRC64; MQRLLFPPLR ALKGRQYLPL LAPRAAPRAQ CDCIRRPLRP GQYSTISEVA LQSGRGTVSL PSKAAERVVG RWLLVCSGTV AGAVILGGVT RLTESGLSMV DWHLIKEMKP PTSQEEWEAE FQRYQQFPEF KILNHDMTLT EFKFIWYMEY SHRMWGRLVG LVYILPAAYF WRKGWLSRGM KGRVLALCGL VCFQGLLGWY MVKSGLEEKS DSHDIPRVSQ YRLAAHLGSA LVLYCASLWT SLSLLLPPHK LPETHQLLQL RRFAHGTAGL VFLTALSGAF VAGLDAGLVY NSFPKMGESW IPEDLFTFSP ILRNVFENPT MVQFDHRILG ITSVTAITVL YFLSRRIPLP RRTKMAAVTL LALAYTQVGL GISTLLMYVP TPLAATHQSG SLALLTGALW LMNELRRVPK //