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Database: UniProt
Entry: Q96RQ3
LinkDB: Q96RQ3
Original site: Q96RQ3 
ID   MCCA_HUMAN              Reviewed;         725 AA.
AC   Q96RQ3; Q59ES4; Q9H959; Q9NS97;
DT   05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT   30-MAY-2006, sequence version 3.
DT   13-FEB-2019, entry version 196.
DE   RecName: Full=Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial;
DE            Short=MCCase subunit alpha;
DE            EC=6.4.1.4;
DE   AltName: Full=3-methylcrotonyl-CoA carboxylase 1;
DE   AltName: Full=3-methylcrotonyl-CoA carboxylase biotin-containing subunit;
DE   AltName: Full=3-methylcrotonyl-CoA:carbon dioxide ligase subunit alpha;
DE   Flags: Precursor;
GN   Name=MCCC1; Synonyms=MCCA;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], INVOLVEMENT IN MCC1D, AND VARIANTS MCC1D
RP   ARG-325 AND SER-385.
RX   PubMed=11170888; DOI=10.1086/318202;
RA   Gallardo M.E., Desviat L.R., Rodriguez J.M., Esparza-Gordillo J.,
RA   Perez-Cerda C., Perez B., Rodriguez-Pombo P., Criado O., Sanz R.,
RA   Morton D.H., Gibson K.M., Le T.P., Ribes A., Rodriguez de Cordoba S.,
RA   Ugarte M., Penalva M.A.;
RT   "The molecular basis of 3-methylcrotonylglycinuria, a disorder of
RT   leucine catabolism.";
RL   Am. J. Hum. Genet. 68:334-346(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=11401427; DOI=10.1006/geno.2000.6366;
RA   Obata K., Fukuda T., Morishita R., Abe S., Asakawa S., Yamaguchi S.,
RA   Yoshino M., Ihara K., Murayama K., Shigemoto K., Shimizu N., Kondo I.;
RT   "Human biotin-containing subunit of 3-methylcrotonyl-CoA carboxylase
RT   gene (MCCA): cDNA sequence, genomic organization, localization to
RT   chromosomal band 3q27, and expression.";
RL   Genomics 72:145-152(2001).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA], VARIANT MCC1D PHE-535, AND VARIANT
RP   PRO-464.
RX   PubMed=11406611; DOI=10.1093/hmg/10.12.1299;
RA   Holzinger A., Roeschinger W., Lagler F., Mayerhofer P.U., Lichtner P.,
RA   Kattenfeld T., Thuy L.P., Nyhan W.L., Koch H.G., Muntau A.C.,
RA   Roscher A.A.;
RT   "Cloning of the human MCCA and MCCB genes and mutations therein reveal
RT   the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency.";
RL   Hum. Mol. Genet. 10:1299-1306(2001).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MCC1D VAL-289; SER-385; PRO-437
RP   AND HIS-532, AND VARIANT PRO-464.
RX   PubMed=11181649; DOI=10.1172/JCI11948;
RA   Baumgartner M.R., Almashanu S., Suormala T., Obie C., Cole R.N.,
RA   Packman S., Baumgartner E.R., Valle D.;
RT   "The molecular basis of human 3-methylcrotonyl-CoA carboxylase
RT   deficiency.";
RL   J. Clin. Invest. 107:495-504(2001).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT PRO-464.
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.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   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.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., 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   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT MCC1D TRP-232, AND
RP   VARIANT PRO-464.
RC   TISSUE=Aorta;
RA   Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA   Ohara O., Nagase T., Kikuno R.F.;
RL   Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT PRO-464.
RC   TISSUE=Skeletal muscle;
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
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [8]
RP   PROTEIN SEQUENCE OF 42-47, AND SUBCELLULAR LOCATION.
RC   TISSUE=Kidney;
RX   PubMed=16023992; DOI=10.1016/j.bbrc.2005.06.190;
RA   Stadler S.C., Polanetz R., Meier S., Mayerhofer P.U., Herrmann J.M.,
RA   Anslinger K., Roscher A.A., Roschinger W., Holzinger A.;
RT   "Mitochondrial targeting signals and mature peptides of 3-
RT   methylcrotonyl-CoA carboxylase.";
RL   Biochem. Biophys. Res. Commun. 334:939-946(2005).
RN   [9]
RP   FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX   PubMed=17360195; DOI=10.1016/j.pep.2007.01.012;
RA   Chu C.H., Cheng D.;
RT   "Expression, purification, characterization of human 3-methylcrotonyl-
RT   CoA carboxylase (MCCC).";
RL   Protein Expr. Purif. 53:421-427(2007).
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.,
RA   Buerckstuemmer T., 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   INTERACTION WITH SIRT4.
RX   PubMed=23438705; DOI=10.1016/j.mito.2013.02.002;
RA   Wirth M., Karaca S., Wenzel D., Ho L., Tishkoff D., Lombard D.B.,
RA   Verdin E., Urlaub H., Jedrusik-Bode M., Fischle W.;
RT   "Mitochondrial SIRT4-type proteins in Caenorhabditis elegans and
RT   mammals interact with pyruvate carboxylase and other acetylated
RT   biotin-dependent carboxylases.";
RL   Mitochondrion 13:705-720(2013).
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.,
RA   Wang L., Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human
RT   liver 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.,
RA   Ayoub D., 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   [14]
RP   STRUCTURE BY NMR OF 640-725.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of RSGI RUH-072, an apo-biotinyl domain from human
RT   acetyl coenzyme A carboxylase.";
RL   Submitted (SEP-2007) to the PDB data bank.
RN   [15]
RP   VARIANTS MCC1D LYS-134; PRO-187; TRP-232; VAL-291 AND SER-385, AND
RP   CHARACTERIZATION OF VARIANT MCC1D VAL-291.
RX   PubMed=16010683; DOI=10.1002/humu.9352;
RA   Dantas M.F., Suormala T., Randolph A., Coelho D., Fowler B., Valle D.,
RA   Baumgartner M.R.;
RT   "3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28
RT   probands, 9 symptomatic and 19 detected by newborn screening.";
RL   Hum. Mutat. 26:164-174(2005).
RN   [16]
RP   VARIANT MCC1D MET-460.
RX   PubMed=17968484; DOI=10.1007/s10038-007-0211-9;
RA   Uematsu M., Sakamoto O., Sugawara N., Kumagai N., Morimoto T.,
RA   Yamaguchi S., Hasegawa Y., Kobayashi H., Ihara K., Yoshino M.,
RA   Watanabe Y., Inokuchi T., Yokoyama T., Kiwaki K., Nakamura K.,
RA   Endo F., Tsuchiya S., Ohura T.;
RT   "Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA
RT   carboxylase deficiency.";
RL   J. Hum. Genet. 52:1040-1043(2007).
RN   [17]
RP   VARIANT MCC1D GLU-46.
RX   PubMed=21071250; DOI=10.1016/j.ymgme.2010.10.008;
RA   Nguyen K.V., Naviaux R.K., Patra S., Barshop B.A., Nyhan W.L.;
RT   "Novel mutations in the human MCCA and MCCB gene causing
RT   methylcrotonylglycinuria.";
RL   Mol. Genet. Metab. 102:218-221(2011).
RN   [18]
RP   VARIANTS MCC1D ARG-276 AND GLN-281.
RX   PubMed=22150417; DOI=10.1111/j.1399-0004.2011.01704.x;
RA   Cho S.Y., Park H.D., Lee Y.W., Ki C.S., Lee S.Y., Sohn Y.B.,
RA   Park S.W., Kim S.H., Ji S., Kim S.J., Choi E.W., Kim C.H., Ko A.R.,
RA   Paik K.H., Lee D.H., Jin D.K.;
RT   "Mutational spectrum in eight Korean patients with 3-methylcrotonyl-
RT   CoA carboxylase deficiency.";
RL   Clin. Genet. 81:96-98(2012).
RN   [19]
RP   VARIANTS MCC1D LYS-56; GLN-281; PRO-380 AND SER-385.
RX   PubMed=22264772; DOI=10.1016/j.ymgme.2011.12.018;
RA   Morscher R.J., Grunert S.C., Burer C., Burda P., Suormala T.,
RA   Fowler B., Baumgartner M.R.;
RT   "A single mutation in MCCC1 or MCCC2 as a potential cause of positive
RT   screening for 3-methylcrotonyl-CoA carboxylase deficiency.";
RL   Mol. Genet. Metab. 105:602-606(2012).
RN   [20]
RP   VARIANTS MCC1D GLU-46; LYS-56; LEU-65; HIS-123; MET-125; LYS-134;
RP   ARG-160; VAL-180; PRO-187; TRP-232; ASP-268; GLN-281; GLY-288;
RP   VAL-289; VAL-291; ARG-325; PRO-372; ASP-379; SER-379; PRO-380;
RP   SER-385; MET-434; MET-439; MET-460; HIS-532; PHE-535 AND
RP   566-VAL-THR-567 DEL, AND CHARACTERIZATION OF VARIANTS MCC1D GLY-288;
RP   ASP-379 AND MET-434.
RX   PubMed=22642865; DOI=10.1186/1750-1172-7-31;
RA   Gruenert S.C., Stucki M., Morscher R.J., Suormala T., Buerer C.,
RA   Burda P., Christensen E., Ficicioglu C., Herwig J., Koelker S.,
RA   Moeslinger D., Pasquini E., Santer R., Schwab K.O., Wilcken B.,
RA   Fowler B., Yue W.W., Baumgartner M.R.;
RT   "3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical,
RT   enzymatic and molecular studies in 88 individuals.";
RL   Orphanet J. Rare Dis. 7:31-54(2012).
RN   [21]
RP   VARIANTS MCC1D CYS-79; VAL-209; GLY-288; LYS-366 AND HIS-444.
RX   PubMed=25382614; DOI=10.1111/cge.12535;
RA   Yang L., Yang J., Zhang T., Weng C., Hong F., Tong F., Yang R.,
RA   Yin X., Yu P., Huang X., Qi M.;
RT   "Identification of eight novel mutations and transcript analysis of
RT   two splicing mutations in Chinese newborns with MCC deficiency.";
RL   Clin. Genet. 88:484-488(2015).
RN   [22]
RP   VARIANTS MCC1D PHE-120; SER-130; LYS-383 AND SER-385.
RX   PubMed=27601257; DOI=10.1016/j.gene.2016.09.003;
RA   Fonseca H., Azevedo L., Serrano C., Sousa C., Marcao A., Vilarinho L.;
RT   "3-Methylcrotonyl-CoA carboxylase deficiency: Mutational spectrum
RT   derived from comprehensive newborn screening.";
RL   Gene 594:203-210(2016).
RN   [23]
RP   VARIANT SER-632.
RX   PubMed=28887846; DOI=10.1002/humu.23335;
RA   Zhou X.L., He L.X., Yu L.J., Wang Y., Wang X.J., Wang E.D., Yang T.;
RT   "Mutations in KARS cause early-onset hearing loss and
RT   leukoencephalopathy: Potential pathogenic mechanism.";
RL   Hum. Mutat. 38:1740-1750(2017).
CC   -!- FUNCTION: Biotin-attachment subunit of the 3-methylcrotonyl-CoA
CC       carboxylase, an enzyme that catalyzes the conversion of 3-
CC       methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for
CC       leucine and isovaleric acid catabolism.
CC       {ECO:0000269|PubMed:17360195}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3-methylbut-2-enoyl-CoA + ATP + hydrogencarbonate = ADP +
CC         H(+) + phosphate + trans-3-methylglutaconyl-CoA;
CC         Xref=Rhea:RHEA:13589, ChEBI:CHEBI:15378, ChEBI:CHEBI:17544,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57344,
CC         ChEBI:CHEBI:57346, ChEBI:CHEBI:456216; EC=6.4.1.4;
CC         Evidence={ECO:0000269|PubMed:17360195};
CC   -!- COFACTOR:
CC       Name=biotin; Xref=ChEBI:CHEBI:57586;
CC   -!- PATHWAY: Amino-acid degradation; L-leucine degradation; (S)-3-
CC       hydroxy-3-methylglutaryl-CoA from 3-isovaleryl-CoA: step 2/3.
CC   -!- SUBUNIT: Probably a dodecamer composed of six biotin-containing
CC       alpha subunits (MCCC1) and six beta (MCCC2) subunits
CC       (PubMed:17360195). Interacts (via the biotin carboxylation domain)
CC       with SIRT4 (PubMed:23438705). {ECO:0000269|PubMed:17360195,
CC       ECO:0000269|PubMed:23438705}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC       {ECO:0000269|PubMed:16023992}.
CC   -!- PTM: Acetylated. {ECO:0000250|UniProtKB:Q99MR8}.
CC   -!- DISEASE: 3-methylcrotonoyl-CoA carboxylase 1 deficiency (MCC1D)
CC       [MIM:210200]: An autosomal recessive disorder of leucine
CC       catabolism. The phenotype is variable, ranging from neonatal onset
CC       with severe neurological involvement to asymptomatic adults. There
CC       is a characteristic organic aciduria with massive excretion of 3-
CC       hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in
CC       combination with a severe secondary carnitine deficiency.
CC       {ECO:0000269|PubMed:11170888, ECO:0000269|PubMed:11181649,
CC       ECO:0000269|PubMed:11406611, ECO:0000269|PubMed:16010683,
CC       ECO:0000269|PubMed:17968484, ECO:0000269|PubMed:21071250,
CC       ECO:0000269|PubMed:22150417, ECO:0000269|PubMed:22264772,
CC       ECO:0000269|PubMed:22642865, ECO:0000269|PubMed:25382614,
CC       ECO:0000269|PubMed:27601257, ECO:0000269|Ref.6}. Note=The disease
CC       is caused by mutations affecting the gene represented in this
CC       entry.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAD92974.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
DR   EMBL; AF310972; AAG53095.1; -; mRNA.
DR   EMBL; AB029826; BAA99407.1; -; mRNA.
DR   EMBL; AF297332; AAK67986.1; -; mRNA.
DR   EMBL; AF310339; AAG50245.1; -; mRNA.
DR   EMBL; AK023051; BAB14377.1; -; mRNA.
DR   EMBL; AB209737; BAD92974.1; ALT_INIT; mRNA.
DR   EMBL; BC004214; AAH04214.1; -; mRNA.
DR   EMBL; BC004187; AAH04187.1; -; mRNA.
DR   CCDS; CCDS3241.1; -.
DR   RefSeq; NP_001280202.1; NM_001293273.1.
DR   RefSeq; NP_064551.3; NM_020166.4.
DR   UniGene; Hs.47649; -.
DR   PDB; 2EJM; NMR; -; A=640-725.
DR   PDBsum; 2EJM; -.
DR   ProteinModelPortal; Q96RQ3; -.
DR   SMR; Q96RQ3; -.
DR   BioGrid; 121249; 37.
DR   CORUM; Q96RQ3; -.
DR   IntAct; Q96RQ3; 13.
DR   MINT; Q96RQ3; -.
DR   STRING; 9606.ENSP00000265594; -.
DR   DrugBank; DB00121; Biotin.
DR   iPTMnet; Q96RQ3; -.
DR   PhosphoSitePlus; Q96RQ3; -.
DR   SwissPalm; Q96RQ3; -.
DR   BioMuta; MCCC1; -.
DR   DMDM; 108861983; -.
DR   EPD; Q96RQ3; -.
DR   jPOST; Q96RQ3; -.
DR   MaxQB; Q96RQ3; -.
DR   PaxDb; Q96RQ3; -.
DR   PeptideAtlas; Q96RQ3; -.
DR   PRIDE; Q96RQ3; -.
DR   ProteomicsDB; 78003; -.
DR   Ensembl; ENST00000265594; ENSP00000265594; ENSG00000078070.
DR   GeneID; 56922; -.
DR   KEGG; hsa:56922; -.
DR   UCSC; uc003fle.4; human.
DR   CTD; 56922; -.
DR   DisGeNET; 56922; -.
DR   EuPathDB; HostDB:ENSG00000078070.11; -.
DR   GeneCards; MCCC1; -.
DR   HGNC; HGNC:6936; MCCC1.
DR   HPA; HPA008310; -.
DR   MalaCards; MCCC1; -.
DR   MIM; 210200; phenotype.
DR   MIM; 609010; gene.
DR   neXtProt; NX_Q96RQ3; -.
DR   OpenTargets; ENSG00000078070; -.
DR   Orphanet; 6; 3-methylcrotonyl-CoA carboxylase deficiency.
DR   PharmGKB; PA30680; -.
DR   eggNOG; KOG0238; Eukaryota.
DR   eggNOG; COG4770; LUCA.
DR   GeneTree; ENSGT00940000156941; -.
DR   HOGENOM; HOG000008989; -.
DR   HOVERGEN; HBG000555; -.
DR   InParanoid; Q96RQ3; -.
DR   KO; K01968; -.
DR   OMA; NVHTNFI; -.
DR   OrthoDB; 254436at2759; -.
DR   PhylomeDB; Q96RQ3; -.
DR   TreeFam; TF105650; -.
DR   BioCyc; MetaCyc:ENSG00000078070-MONOMER; -.
DR   Reactome; R-HSA-196780; Biotin transport and metabolism.
DR   Reactome; R-HSA-3371599; Defective HLCS causes multiple carboxylase deficiency.
DR   Reactome; R-HSA-70895; Branched-chain amino acid catabolism.
DR   UniPathway; UPA00363; UER00861.
DR   ChiTaRS; MCCC1; human.
DR   EvolutionaryTrace; Q96RQ3; -.
DR   GenomeRNAi; 56922; -.
DR   PRO; PR:Q96RQ3; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   Bgee; ENSG00000078070; Expressed in 218 organ(s), highest expression level in body of pancreas.
DR   ExpressionAtlas; Q96RQ3; baseline and differential.
DR   Genevisible; Q96RQ3; HS.
DR   GO; GO:0002169; C:3-methylcrotonyl-CoA carboxylase complex, mitochondrial; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:1905202; C:methylcrotonoyl-CoA carboxylase complex; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005759; C:mitochondrial matrix; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0009374; F:biotin binding; NAS:UniProtKB.
DR   GO; GO:0004075; F:biotin carboxylase activity; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0046872; F:metal ion binding; IEA:InterPro.
DR   GO; GO:0004485; F:methylcrotonoyl-CoA carboxylase activity; IEA:UniProtKB-EC.
DR   GO; GO:0006768; P:biotin metabolic process; TAS:Reactome.
DR   GO; GO:0006552; P:leucine catabolic process; ISS:ParkinsonsUK-UCL.
DR   GO; GO:0051291; P:protein heterooligomerization; NAS:ParkinsonsUK-UCL.
DR   Gene3D; 3.30.1490.20; -; 1.
DR   InterPro; IPR011761; ATP-grasp.
DR   InterPro; IPR013815; ATP_grasp_subdomain_1.
DR   InterPro; IPR005481; BC-like_N.
DR   InterPro; IPR001882; Biotin_BS.
DR   InterPro; IPR011764; Biotin_carboxylation_dom.
DR   InterPro; IPR005482; Biotin_COase_C.
DR   InterPro; IPR000089; Biotin_lipoyl.
DR   InterPro; IPR005479; CbamoylP_synth_lsu-like_ATP-bd.
DR   InterPro; IPR016185; PreATP-grasp_dom_sf.
DR   InterPro; IPR011054; Rudment_hybrid_motif.
DR   InterPro; IPR011053; Single_hybrid_motif.
DR   Pfam; PF02785; Biotin_carb_C; 1.
DR   Pfam; PF00289; Biotin_carb_N; 1.
DR   Pfam; PF00364; Biotin_lipoyl; 1.
DR   Pfam; PF02786; CPSase_L_D2; 1.
DR   SMART; SM00878; Biotin_carb_C; 1.
DR   SUPFAM; SSF51230; SSF51230; 1.
DR   SUPFAM; SSF51246; SSF51246; 1.
DR   SUPFAM; SSF52440; SSF52440; 1.
DR   PROSITE; PS50975; ATP_GRASP; 1.
DR   PROSITE; PS50979; BC; 1.
DR   PROSITE; PS00188; BIOTIN; 1.
DR   PROSITE; PS50968; BIOTINYL_LIPOYL; 1.
DR   PROSITE; PS00867; CPSASE_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; ATP-binding; Biotin; Complete proteome;
KW   Direct protein sequencing; Disease mutation; Ligase; Mitochondrion;
KW   Nucleotide-binding; Polymorphism; Reference proteome; Transit peptide.
FT   TRANSIT       1     41       Mitochondrion.
FT                                {ECO:0000269|PubMed:16023992}.
FT   CHAIN        42    725       Methylcrotonoyl-CoA carboxylase subunit
FT                                alpha, mitochondrial.
FT                                /FTId=PRO_0000002833.
FT   DOMAIN       48    494       Biotin carboxylation.
FT   DOMAIN      167    364       ATP-grasp. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00409}.
FT   DOMAIN      643    715       Biotinyl-binding. {ECO:0000255|PROSITE-
FT                                ProRule:PRU01066}.
FT   ACT_SITE    339    339       {ECO:0000250}.
FT   BINDING     163    163       ATP. {ECO:0000250}.
FT   BINDING     247    247       ATP. {ECO:0000250}.
FT   BINDING     282    282       ATP. {ECO:0000250}.
FT   MOD_RES     237    237       N6-acetyllysine.
FT                                {ECO:0000250|UniProtKB:Q99MR8}.
FT   MOD_RES     494    494       N6-acetyllysine.
FT                                {ECO:0000250|UniProtKB:Q99MR8}.
FT   MOD_RES     581    581       N6-acetyllysine; alternate.
FT                                {ECO:0000250|UniProtKB:Q99MR8}.
FT   MOD_RES     581    581       N6-succinyllysine; alternate.
FT                                {ECO:0000250|UniProtKB:Q99MR8}.
FT   MOD_RES     681    681       N6-biotinyllysine. {ECO:0000250,
FT                                ECO:0000255|PROSITE-ProRule:PRU01066}.
FT   VARIANT      46     46       G -> E (in MCC1D; dbSNP:rs199517715).
FT                                {ECO:0000269|PubMed:21071250,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072486.
FT   VARIANT      56     56       N -> K (in MCC1D; dbSNP:rs1057520695).
FT                                {ECO:0000269|PubMed:22264772,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072487.
FT   VARIANT      65     65       M -> L (in MCC1D).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072488.
FT   VARIANT      79     79       Y -> C (in MCC1D).
FT                                {ECO:0000269|PubMed:25382614}.
FT                                /FTId=VAR_077284.
FT   VARIANT     120    120       S -> F (in MCC1D).
FT                                {ECO:0000269|PubMed:27601257}.
FT                                /FTId=VAR_077285.
FT   VARIANT     123    123       Q -> H (in MCC1D).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072489.
FT   VARIANT     125    125       I -> M (in MCC1D).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072490.
FT   VARIANT     130    130       G -> S (in MCC1D; clinically asymptomatic
FT                                form; dbSNP:rs202197951).
FT                                {ECO:0000269|PubMed:27601257}.
FT                                /FTId=VAR_077286.
FT   VARIANT     134    134       E -> K (in MCC1D; dbSNP:rs1229069160).
FT                                {ECO:0000269|PubMed:16010683,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072491.
FT   VARIANT     160    160       M -> R (in MCC1D).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072492.
FT   VARIANT     180    180       G -> V (in MCC1D; dbSNP:rs748201122).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072493.
FT   VARIANT     187    187       S -> P (in MCC1D; dbSNP:rs757362635).
FT                                {ECO:0000269|PubMed:16010683,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072494.
FT   VARIANT     209    209       G -> V (in MCC1D; dbSNP:rs186209189).
FT                                {ECO:0000269|PubMed:25382614}.
FT                                /FTId=VAR_077287.
FT   VARIANT     232    232       R -> W (in MCC1D; dbSNP:rs727504004).
FT                                {ECO:0000269|PubMed:16010683,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072495.
FT   VARIANT     268    268       A -> D (in MCC1D).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072496.
FT   VARIANT     276    276       C -> R (in MCC1D; dbSNP:rs773433541).
FT                                {ECO:0000269|PubMed:22150417}.
FT                                /FTId=VAR_067197.
FT   VARIANT     281    281       R -> Q (in MCC1D; dbSNP:rs754437245).
FT                                {ECO:0000269|PubMed:22150417,
FT                                ECO:0000269|PubMed:22264772,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_067198.
FT   VARIANT     288    288       E -> G (in MCC1D; shows no residual
FT                                activity; dbSNP:rs746500530).
FT                                {ECO:0000269|PubMed:22642865,
FT                                ECO:0000269|PubMed:25382614}.
FT                                /FTId=VAR_072497.
FT   VARIANT     289    289       A -> V (in MCC1D; mild form;
FT                                dbSNP:rs1326114075).
FT                                {ECO:0000269|PubMed:11181649,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_012785.
FT   VARIANT     291    291       A -> V (in MCC1D; associated with a
FT                                reduction of wild-type residual activity;
FT                                dbSNP:rs201041864).
FT                                {ECO:0000269|PubMed:16010683,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072498.
FT   VARIANT     325    325       M -> R (in MCC1D; dbSNP:rs119103212).
FT                                {ECO:0000269|PubMed:11170888,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_012786.
FT   VARIANT     366    366       E -> K (in MCC1D; unknown pathological
FT                                significance; dbSNP:rs201386261).
FT                                {ECO:0000269|PubMed:25382614}.
FT                                /FTId=VAR_077288.
FT   VARIANT     372    372       Q -> P (in MCC1D; dbSNP:rs755328329).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072499.
FT   VARIANT     379    379       G -> D (in MCC1D).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072500.
FT   VARIANT     379    379       G -> S (in MCC1D; dbSNP:rs887877405).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072501.
FT   VARIANT     380    380       H -> P (in MCC1D; dbSNP:rs794727036).
FT                                {ECO:0000269|PubMed:22264772,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072502.
FT   VARIANT     383    383       E -> K (in MCC1D; unknown pathological
FT                                significance; dbSNP:rs1333357031).
FT                                {ECO:0000269|PubMed:27601257}.
FT                                /FTId=VAR_077289.
FT   VARIANT     385    385       R -> S (in MCC1D; severe form;
FT                                dbSNP:rs119103213).
FT                                {ECO:0000269|PubMed:11170888,
FT                                ECO:0000269|PubMed:11181649,
FT                                ECO:0000269|PubMed:16010683,
FT                                ECO:0000269|PubMed:22264772,
FT                                ECO:0000269|PubMed:22642865,
FT                                ECO:0000269|PubMed:27601257}.
FT                                /FTId=VAR_012787.
FT   VARIANT     434    434       I -> M (in MCC1D; shows some wild-type
FT                                residual activity; dbSNP:rs376289130).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072503.
FT   VARIANT     437    437       L -> P (in MCC1D; severe form;
FT                                dbSNP:rs119103215).
FT                                {ECO:0000269|PubMed:11181649}.
FT                                /FTId=VAR_012788.
FT   VARIANT     439    439       V -> M (in MCC1D; dbSNP:rs398124352).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072504.
FT   VARIANT     444    444       R -> H (in MCC1D; dbSNP:rs768785753).
FT                                {ECO:0000269|PubMed:25382614}.
FT                                /FTId=VAR_077290.
FT   VARIANT     460    460       I -> M (in MCC1D; dbSNP:rs119103218).
FT                                {ECO:0000269|PubMed:17968484,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072505.
FT   VARIANT     464    464       H -> P (in dbSNP:rs2270968).
FT                                {ECO:0000269|PubMed:11181649,
FT                                ECO:0000269|PubMed:11406611,
FT                                ECO:0000269|PubMed:14702039,
FT                                ECO:0000269|PubMed:15489334,
FT                                ECO:0000269|Ref.6}.
FT                                /FTId=VAR_012789.
FT   VARIANT     532    532       D -> H (in MCC1D; severe form;
FT                                dbSNP:rs119103214).
FT                                {ECO:0000269|PubMed:11181649,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_012790.
FT   VARIANT     535    535       S -> F (in MCC1D; asymptomatic form;
FT                                dbSNP:rs119103216).
FT                                {ECO:0000269|PubMed:11406611,
FT                                ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_012791.
FT   VARIANT     560    560       N -> T (in dbSNP:rs35219417).
FT                                /FTId=VAR_038631.
FT   VARIANT     566    567       Missing (in MCC1D).
FT                                {ECO:0000269|PubMed:22642865}.
FT                                /FTId=VAR_072506.
FT   VARIANT     632    632       P -> S (in dbSNP:rs142867987).
FT                                {ECO:0000269|PubMed:28887846}.
FT                                /FTId=VAR_079752.
FT   CONFLICT    469    469       F -> L (in Ref. 3; AAK67986).
FT                                {ECO:0000305}.
FT   STRAND      652    660       {ECO:0000244|PDB:2EJM}.
FT   STRAND      666    668       {ECO:0000244|PDB:2EJM}.
FT   STRAND      673    687       {ECO:0000244|PDB:2EJM}.
FT   STRAND      692    698       {ECO:0000244|PDB:2EJM}.
FT   STRAND      703    705       {ECO:0000244|PDB:2EJM}.
FT   STRAND      712    714       {ECO:0000244|PDB:2EJM}.
SQ   SEQUENCE   725 AA;  80473 MW;  B84AD23806035A40 CRC64;
     MAAASAVSVL LVAAERNRWH RLPSLLLPPR TWVWRQRTMK YTTATGRNIT KVLIANRGEI
     ACRVMRTAKK LGVQTVAVYS EADRNSMHVD MADEAYSIGP APSQQSYLSM EKIIQVAKTS
     AAQAIHPGCG FLSENMEFAE LCKQEGIIFI GPPPSAIRDM GIKSTSKSIM AAAGVPVVEG
     YHGEDQSDQC LKEHARRIGY PVMIKAVRGG GGKGMRIVRS EQEFQEQLES ARREAKKSFN
     DDAMLIEKFV DTPRHVEVQV FGDHHGNAVY LFERDCSVQR RHQKIIEEAP APGIKSEVRK
     KLGEAAVRAA KAVNYVGAGT VEFIMDSKHN FCFMEMNTRL QVEHPVTEMI TGTDLVEWQL
     RIAAGEKIPL SQEEITLQGH AFEARIYAED PSNNFMPVAG PLVHLSTPRA DPSTRIETGV
     RQGDEVSVHY DPMIAKLVVW AADRQAALTK LRYSLRQYNI VGLHTNIDFL LNLSGHPEFE
     AGNVHTDFIP QHHKQLLLSR KAAAKESLCQ AALGLILKEK AMTDTFTLQA HDQFSPFSSS
     SGRRLNISYT RNMTLKDGKN NVAIAVTYNH DGSYSMQIED KTFQVLGNLY SEGDCTYLKC
     SVNGVASKAK LIILENTIYL FSKEGSIEID IPVPKYLSSV SSQETQGGPL APMTGTIEKV
     FVKAGDKVKA GDSLMVMIAM KMEHTIKSPK DGTVKKVFYR EGAQANRHTP LVEFEEEESD
     KRESE
//
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