ID   COA8_HUMAN              Reviewed;         206 AA.
AC   Q96IL0; H7C2Z1; Q53G28;
DT   19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT   14-DEC-2011, sequence version 3.
DT   24-JAN-2024, entry version 141.
DE   RecName: Full=Cytochrome c oxidase assembly factor 8 {ECO:0000305};
DE            Short=COA8 {ECO:0000305};
DE   AltName: Full=Apoptogenic protein 1, mitochondrial;
DE            Short=APOP-1;
DE   Flags: Precursor;
GN   Name=COA8 {ECO:0000312|HGNC:HGNC:20492};
GN   Synonyms=APOP1, APOPT1 {ECO:0000312|HGNC:HGNC:20492}, C14orf153;
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 [LARGE SCALE GENOMIC DNA].
RX   PubMed=12508121; DOI=10.1038/nature01348;
RA   Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA   Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA   Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA   Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA   Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA   Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA   Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA   Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA   Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA   Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA   Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA   Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA   Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA   Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA   Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA   Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA   Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA   Waterston R., Hood L., Weissenbach J.;
RT   "The DNA sequence and analysis of human chromosome 14.";
RL   Nature 421:601-607(2003).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-197.
RC   TISSUE=Ovary;
RX   PubMed=16712791; DOI=10.1016/j.bbrc.2006.04.175;
RA   Wang A.G., Yoon S.Y., Oh J.H., Jeon Y.J., Kim M., Kim J.M., Byun S.S.,
RA   Yang J.O., Kim J.H., Kim D.G., Yeom Y.I., Yoo H.S., Kim Y.S., Kim N.S.;
RT   "Identification of intrahepatic cholangiocarcinoma related genes by
RT   comparison with normal liver tissues using expressed sequence tags.";
RL   Biochem. Biophys. Res. Commun. 345:1022-1032(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 9-206.
RA   Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA   Tanaka A., Yokoyama S.;
RL   Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 12-206, AND VARIANT ALA-27.
RC   TISSUE=Ovary;
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   FUNCTION, SUBCELLULAR LOCATION, ALTERNATIVE SPLICING, CHARACTERIZATION OF
RP   VARIANT MC4DN17 79-ARG--ASN-206 DEL, AND PROTEASOMAL DEGRADATION.
RX   PubMed=30552096; DOI=10.15252/emmm.201809582;
RA   Signes A., Cerutti R., Dickson A.S., Beninca C., Hinchy E.C., Ghezzi D.,
RA   Carrozzo R., Bertini E., Murphy M.P., Nathan J.A., Viscomi C.,
RA   Fernandez-Vizarra E., Zeviani M.;
RT   "APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and
RT   ROS.";
RL   EMBO Mol. Med. 11:0-0(2019).
RN   [6]
RP   VARIANTS MC4DN17 79-ARG--ASN-206 DEL; SER-118 AND GLU-124 DEL,
RP   CHARACTERIZATION OF VARIANT MC4DN17 79-ARG--ASN-206 DEL, INVOLVEMENT IN
RP   MC4DN17, SUBCELLULAR LOCATION, CLEAVAGE, FUNCTION, INDUCTION BY OXIDATIVE
RP   STRESS, AND TISSUE SPECIFICITY.
RX   PubMed=25175347; DOI=10.1016/j.ajhg.2014.08.003;
RA   Melchionda L., Haack T.B., Hardy S., Abbink T.E., Fernandez-Vizarra E.,
RA   Lamantea E., Marchet S., Morandi L., Moggio M., Carrozzo R., Torraco A.,
RA   Diodato D., Strom T.M., Meitinger T., Tekturk P., Yapici Z.,
RA   Al-Murshedi F., Stevens R., Rodenburg R.J., Lamperti C., Ardissone A.,
RA   Moroni I., Uziel G., Prokisch H., Taylor R.W., Bertini E.,
RA   van der Knaap M.S., Ghezzi D., Zeviani M.;
RT   "Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating
RT   leukoencephalopathy with cytochrome c oxidase deficiency.";
RL   Am. J. Hum. Genet. 95:315-325(2014).
RN   [7]
RP   INVOLVEMENT IN MC4DN17.
RX   PubMed=29577824; DOI=10.1177/0883073818760875;
RA   Sharma S., Singh P., Fernandez-Vizarra E., Zeviani M., Van der Knaap M.S.,
RA   Saran R.K.;
RT   "Cavitating Leukoencephalopathy With Posterior Predominance Caused by a
RT   Deletion in the APOPT1 Gene in an Indian Boy.";
RL   J. Child Neurol. 33:428-431(2018).
CC   -!- FUNCTION: Required for cytochrome c complex (COX) IV assembly and
CC       function Protects COX assembly from oxidation-induced degradation, COX
CC       being the terminal component of the mitochondrial respiratory chain.
CC       {ECO:0000269|PubMed:25175347, ECO:0000269|PubMed:30552096}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC       {ECO:0000269|PubMed:25175347, ECO:0000269|PubMed:30552096}; Peripheral
CC       membrane protein {ECO:0000305|PubMed:30552096}; Matrix side
CC       {ECO:0000269|PubMed:30552096}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q96IL0-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q96IL0-2; Sequence=VSP_060246, VSP_060247;
CC   -!- TISSUE SPECIFICITY: Expressed in fibroblasts.
CC       {ECO:0000269|PubMed:25175347}.
CC   -!- INDUCTION: In conditions of increased oxidative stress, the protein is
CC       stabilized, increasing its mature intramitochondrial form and thereby
CC       protecting COX from oxidatively induced degradation.
CC       {ECO:0000269|PubMed:25175347, ECO:0000269|PubMed:30552096}.
CC   -!- PTM: N-terminal mitochondrial targeting sequence is cleaved from the
CC       mature protein once in the mitochondrion. {ECO:0000269|PubMed:25175347,
CC       ECO:0000269|PubMed:30552096}.
CC   -!- PTM: In normal conditions, the cytoplasmic precursor protein is rapidly
CC       degraded by the ubiquitination-proteasome system (UPS). Oxidative
CC       stress induces protein stabilization and import into mitochondria where
CC       it protects COX from degradation. {ECO:0000269|PubMed:25175347,
CC       ECO:0000269|PubMed:30552096}.
CC   -!- DISEASE: Mitochondrial complex IV deficiency, nuclear type 17 (MC4DN17)
CC       [MIM:619061]: An autosomal recessive mitochondrial disorder with highly
CC       variable clinical manifestations and severity. Clinical features vary
CC       from acute neurometabolic decompensation in late infancy to subtle
CC       neurological signs presenting in adolescence. Encephalopathic episodes
CC       are characterized by acute loss of developmental milestones including
CC       ability to walk or sit, loss of speech, episodes with somnolence and
CC       seizure, and pyramidal signs rapidly evolving into spastic
CC       tetraparesis. The clinical course subsequently tends to stabilize and
CC       in several subjects marked recovery of neurological milestones is
CC       observed over time. Brain imaging shows a cavitating leukodystrophy,
CC       predominantly involving the posterior cerebral white matter and the
CC       corpus callosum in the acute stage, after which the abnormalities
CC       partially improve and then stabilize. Patient tissues show variably
CC       decreased levels and activity of mitochondrial respiratory complex IV.
CC       {ECO:0000269|PubMed:25175347, ECO:0000269|PubMed:29577824,
CC       ECO:0000269|PubMed:30552096}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: [Isoform 2]: Protein may not fold correctly and may be
CC       rapidly degraded. {ECO:0000303|PubMed:30552096}.
CC   -!- SIMILARITY: Belongs to the COA8 family. {ECO:0000305}.
CC   -!- CAUTION: It is uncertain whether Met-1 or Met-14 is the initiator.
CC       However, according to some experiments, Met-14 seems to be the
CC       initiator. {ECO:0000305|PubMed:25175347, ECO:0000305|PubMed:30552096}.
CC   -!- CAUTION: First thought to play a role in the regulation of apoptosis,
CC       mediating mitochondria-induced cell death in vascular smooth muscle
CC       cells through the release of cytochrome c (COX) from mitochondria and
CC       the activation of the caspase cascade (By similarity). However, recent
CC       studies show that it is not directly involved in apoptosis regulation
CC       but in the protection of COX from oxidatively induced degradation
CC       (PubMed:30552096, PubMed:25175347). {ECO:0000250|UniProtKB:Q9CQW7,
CC       ECO:0000269|PubMed:25175347, ECO:0000269|PubMed:30552096}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH07412.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=BAD96812.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=BAD96823.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AL139300; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CB136383; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AK223092; BAD96812.1; ALT_INIT; mRNA.
DR   EMBL; AK223103; BAD96823.1; ALT_INIT; mRNA.
DR   EMBL; BC007412; AAH07412.1; ALT_INIT; mRNA.
DR   RefSeq; NP_001289581.1; NM_001302652.1.
DR   RefSeq; NP_001289582.1; NM_001302653.1.
DR   RefSeq; NP_115750.2; NM_032374.4.
DR   AlphaFoldDB; Q96IL0; -.
DR   BioGRID; 124058; 12.
DR   IntAct; Q96IL0; 1.
DR   STRING; 9606.ENSP00000386485; -.
DR   iPTMnet; Q96IL0; -.
DR   PhosphoSitePlus; Q96IL0; -.
DR   BioMuta; APOPT1; -.
DR   DMDM; 363548522; -.
DR   EPD; Q96IL0; -.
DR   jPOST; Q96IL0; -.
DR   MassIVE; Q96IL0; -.
DR   MaxQB; Q96IL0; -.
DR   PaxDb; 9606-ENSP00000386485; -.
DR   PeptideAtlas; Q96IL0; -.
DR   ProteomicsDB; 76839; -.
DR   Pumba; Q96IL0; -.
DR   Antibodypedia; 66570; 40 antibodies from 12 providers.
DR   DNASU; 84334; -.
DR   Ensembl; ENST00000674165.1; ENSP00000501341.1; ENSG00000256053.9. [Q96IL0-1]
DR   GeneID; 84334; -.
DR   KEGG; hsa:84334; -.
DR   UCSC; uc010tyc.3; human. [Q96IL0-1]
DR   UCSC; uc059frt.1; human.
DR   AGR; HGNC:20492; -.
DR   CTD; 84334; -.
DR   DisGeNET; 84334; -.
DR   GeneCards; COA8; -.
DR   HGNC; HGNC:20492; COA8.
DR   HPA; ENSG00000256053; Tissue enhanced (skeletal).
DR   MalaCards; COA8; -.
DR   MIM; 616003; gene.
DR   MIM; 619061; phenotype.
DR   neXtProt; NX_Q96IL0; -.
DR   OpenTargets; ENSG00000256053; -.
DR   Orphanet; 436271; Non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy.
DR   PharmGKB; PA134961925; -.
DR   VEuPathDB; HostDB:ENSG00000256053; -.
DR   eggNOG; KOG4094; Eukaryota.
DR   GeneTree; ENSGT00390000008212; -.
DR   HOGENOM; CLU_118274_0_0_1; -.
DR   InParanoid; Q96IL0; -.
DR   OrthoDB; 1352289at2759; -.
DR   PhylomeDB; Q96IL0; -.
DR   TreeFam; TF315168; -.
DR   PathwayCommons; Q96IL0; -.
DR   SignaLink; Q96IL0; -.
DR   BioGRID-ORCS; 84334; 13 hits in 1110 CRISPR screens.
DR   ChiTaRS; APOPT1; human.
DR   GenomeRNAi; 84334; -.
DR   Pharos; Q96IL0; Tdark.
DR   PRO; PR:Q96IL0; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; Q96IL0; Protein.
DR   Bgee; ENSG00000256053; Expressed in left testis and 180 other cell types or tissues.
DR   ExpressionAtlas; Q96IL0; baseline and differential.
DR   GO; GO:0099617; C:matrix side of mitochondrial inner membrane; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IEA:InterPro.
DR   GO; GO:0033617; P:mitochondrial cytochrome c oxidase assembly; IDA:UniProtKB.
DR   GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; IMP:UniProtKB.
DR   GO; GO:1904960; P:positive regulation of cytochrome-c oxidase activity; IDA:UniProtKB.
DR   GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR   GO; GO:0000302; P:response to reactive oxygen species; IDA:UniProtKB.
DR   InterPro; IPR018796; COA8.
DR   PANTHER; PTHR31107; APOPTOGENIC PROTEIN 1, MITOCHONDRIAL; 1.
DR   PANTHER; PTHR31107:SF2; CYTOCHROME C OXIDASE ASSEMBLY FACTOR 8; 1.
DR   Pfam; PF10231; COA8; 1.
DR   Genevisible; Q96IL0; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Apoptosis; Disease variant; Membrane; Mitochondrion;
KW   Mitochondrion inner membrane; Primary mitochondrial disease;
KW   Reference proteome; Transit peptide; Ubl conjugation.
FT   TRANSIT         1..39
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000269|PubMed:25175347"
FT   CHAIN           40..206
FT                   /note="Cytochrome c oxidase assembly factor 8"
FT                   /id="PRO_0000019559"
FT   VAR_SEQ         121..125
FT                   /note="EKEEF -> VRKQH (in isoform 2)"
FT                   /id="VSP_060246"
FT   VAR_SEQ         126..206
FT                   /note="Missing (in isoform 2)"
FT                   /id="VSP_060247"
FT   VARIANT         27
FT                   /note="P -> A (in dbSNP:rs2274268)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_023000"
FT   VARIANT         79..206
FT                   /note="Missing (in MC4DN17; low steady-state levels of COX
FT                   subunits and reduced levels of fully assembled COX; highly
FT                   decreased COX complex IV activity and decreased COX complex
FT                   II activity in muscle)"
FT                   /evidence="ECO:0000269|PubMed:25175347,
FT                   ECO:0000269|PubMed:30552096"
FT                   /id="VAR_082029"
FT   VARIANT         88
FT                   /note="N -> S (in dbSNP:rs35960830)"
FT                   /id="VAR_033745"
FT   VARIANT         118
FT                   /note="F -> S (in MC4DN17; uncertain significance;
FT                   dbSNP:rs587777786)"
FT                   /evidence="ECO:0000269|PubMed:25175347"
FT                   /id="VAR_082030"
FT   VARIANT         124
FT                   /note="Missing (in MC4DN17; dbSNP:rs587777787)"
FT                   /evidence="ECO:0000269|PubMed:25175347"
FT                   /id="VAR_082031"
FT   CONFLICT        191
FT                   /note="E -> G (in Ref. 2; CB136383)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   206 AA;  24153 MW;  7ABC3470215F2244 CRC64;
     MLPCAAGARG RGAMVVLRAG KKTFLPPLCR AFACRGCQLA PERGAERRDT APSGVSRFCP
     PRKSCHDWIG PPDKYSNLRP VHFYIPENES PLEQKLRKLR QETQEWNQQF WANQNLTFSK
     EKEEFIHSRL KTKGLGLRTE SGQKATLNAE EMADFYKEFL SKNFQKHMYY NRDWYKRNFA
     ITFFMGKVAL ERIWNKLKQK QKKRSN
//