Q96RQ3 (MCCA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial
Short name=MCCase subunit alpha
EC=6.4.1.4

Alternative name(s):
3-methylcrotonyl-CoA carboxylase 1
3-methylcrotonyl-CoA carboxylase biotin-containing subunit
3-methylcrotonyl-CoA:carbon dioxide ligase subunit alpha

Gene names

Name:	MCCC1
Synonyms:	MCCA

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	725 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Catalytic activity	ATP + 3-methylcrotonoyl-CoA + HCO3- = ADP + phosphate + 3-methylglutaconyl-CoA.
Cofactor	Biotin.
Pathway	Amino-acid degradation; L-leucine degradation; (S)-3-hydroxy-3-methylglutaryl-CoA from 3-isovaleryl-CoA: step 2/3.
Subunit structure	Probably a dodecamer composed of six biotin-containing alpha subunits and six beta subunits.
Subcellular location	Mitochondrion matrix Ref.8.
Involvement in disease	Methylcrotonoyl-CoA carboxylase 1 deficiency (MCC1D) [MIM:210200]: An autosomal recessive disorder of leucine catabolism. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.3 Ref.4 Ref.11
Sequence similarities	Contains 1 ATP-grasp domain. Contains 1 biotin carboxylation domain. Contains 1 biotinyl-binding domain.
Sequence caution	The sequence BAD92974.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transit peptide
Ligand	ATP-binding Biotin Nucleotide-binding
Molecular function	Ligase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	biotin metabolic process Non-traceable author statement Ref.2. Source: UniProtKB leucine catabolic process Non-traceable author statement Ref.1. Source: UniProtKB
Cellular_component	mitochondrial inner membrane Traceable author statement. Source: Reactome mitochondrial matrix Non-traceable author statement Ref.1. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW biotin binding Non-traceable author statement Ref.2. Source: UniProtKB biotin carboxylase activity Inferred from electronic annotation. Source: InterPro metal ion binding Inferred from electronic annotation. Source: InterPro methylcrotonoyl-CoA carboxylase activity Non-traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 41

41

Mitochondrion Ref.8

Chain

42 – 725

684

Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial

PRO_0000002833

Regions

Domain

48 – 494

447

Biotin carboxylation

Domain

167 – 364

198

ATP-grasp

Domain

629 – 714

86

Biotinyl-binding

Sites

Active site

339

1

By similarity

Binding site

163

1

ATP By similarity

Binding site

247

1

ATP By similarity

Binding site

282

1

ATP By similarity

Amino acid modifications

Modified residue

681

1

N6-biotinyllysine By similarity

Natural variations

Natural variant

276

1

C → R in MCC1D. Ref.11

VAR_067197

Natural variant

281

1

R → Q in MCC1D. Ref.11

VAR_067198

Natural variant

289

1

A → V in MCC1D; mild form. Ref.4

VAR_012785

Natural variant

325

1

M → R in MCC1D. Ref.1

VAR_012786

Natural variant

385

1

R → S in MCC1D; severe form. Ref.1 Ref.4
Corresponds to variant rs28934881 [ dbSNP | Ensembl ].

VAR_012787

Natural variant

437

1

L → P in MCC1D; severe form. Ref.4
Corresponds to variant rs28934882 [ dbSNP | Ensembl ].

VAR_012788

Natural variant

464

1

H → P. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7
Corresponds to variant rs2270968 [ dbSNP | Ensembl ].

VAR_012789

Natural variant

532

1

D → H in MCC1D; severe form. Ref.4

VAR_012790

Natural variant

535

1

S → F in MCC1D; asymptomatic form. Ref.3

VAR_012791

Natural variant

560

1

N → T.
Corresponds to variant rs35219417 [ dbSNP | Ensembl ].

VAR_038631

Experimental info

Sequence conflict

232

1

R → W in BAD92974. Ref.6

Sequence conflict

469

1

F → L in AAK67986. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

725

Helix Strand Turn

Details...

Beta strand

652 – 660

9

Beta strand

666 – 668

3

Beta strand

673 – 687

15

Beta strand

692 – 698

7

Beta strand

703 – 705

3

Beta strand

712 – 714

3

Sequences

	Sequence		Length	Mass (Da)
	Q96RQ3 [UniParc]. Last modified May 30, 2006. Version 3. Checksum: B84AD23806035A40	FASTA	725	80,473
	10 20 30 40 50 60 MAAASAVSVL LVAAERNRWH RLPSLLLPPR TWVWRQRTMK YTTATGRNIT KVLIANRGEI 70 80 90 100 110 120 ACRVMRTAKK LGVQTVAVYS EADRNSMHVD MADEAYSIGP APSQQSYLSM EKIIQVAKTS 130 140 150 160 170 180 AAQAIHPGCG FLSENMEFAE LCKQEGIIFI GPPPSAIRDM GIKSTSKSIM AAAGVPVVEG 190 200 210 220 230 240 YHGEDQSDQC LKEHARRIGY PVMIKAVRGG GGKGMRIVRS EQEFQEQLES ARREAKKSFN 250 260 270 280 290 300 DDAMLIEKFV DTPRHVEVQV FGDHHGNAVY LFERDCSVQR RHQKIIEEAP APGIKSEVRK 310 320 330 340 350 360 KLGEAAVRAA KAVNYVGAGT VEFIMDSKHN FCFMEMNTRL QVEHPVTEMI TGTDLVEWQL 370 380 390 400 410 420 RIAAGEKIPL SQEEITLQGH AFEARIYAED PSNNFMPVAG PLVHLSTPRA DPSTRIETGV 430 440 450 460 470 480 RQGDEVSVHY DPMIAKLVVW AADRQAALTK LRYSLRQYNI VGLHTNIDFL LNLSGHPEFE 490 500 510 520 530 540 AGNVHTDFIP QHHKQLLLSR KAAAKESLCQ AALGLILKEK AMTDTFTLQA HDQFSPFSSS 550 560 570 580 590 600 SGRRLNISYT RNMTLKDGKN NVAIAVTYNH DGSYSMQIED KTFQVLGNLY SEGDCTYLKC 610 620 630 640 650 660 SVNGVASKAK LIILENTIYL FSKEGSIEID IPVPKYLSSV SSQETQGGPL APMTGTIEKV 670 680 690 700 710 720 FVKAGDKVKA GDSLMVMIAM KMEHTIKSPK DGTVKKVFYR EGAQANRHTP LVEFEEEESD KRESE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism." Gallardo M.E., Desviat L.R., Rodriguez J.M., Esparza-Gordillo J., Perez-Cerda C., Perez B., Rodriguez-Pombo P., Criado O., Sanz R., Morton D.H., Gibson K.M., Le T.P., Ribes A., Rodriguez de Cordoba S., Ugarte M., Penalva M.A. Am. J. Hum. Genet. 68:334-346(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MCC1D ARG-325 AND SER-385.
[2]	"Human biotin-containing subunit of 3-methylcrotonyl-CoA carboxylase gene (MCCA): cDNA sequence, genomic organization, localization to chromosomal band 3q27, and expression." Obata K., Fukuda T., Morishita R., Abe S., Asakawa S., Yamaguchi S., Yoshino M., Ihara K., Murayama K., Shigemoto K., Shimizu N., Kondo I. Genomics 72:145-152(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency." Holzinger A., Roeschinger W., Lagler F., Mayerhofer P.U., Lichtner P., Kattenfeld T., Thuy L.P., Nyhan W.L., Koch H.G., Muntau A.C., Roscher A.A. Hum. Mol. Genet. 10:1299-1306(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT MCC1D PHE-535, VARIANT PRO-464.
[4]	"The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency." Baumgartner M.R., Almashanu S., Suormala T., Obie C., Cole R.N., Packman S., Baumgartner E.R., Valle D. J. Clin. Invest. 107:495-504(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MCC1D VAL-289; SER-385; PRO-437 AND HIS-532, VARIANT PRO-464.
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-464.
[6]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-464. Tissue: Aorta.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-464. Tissue: Skeletal muscle.
[8]	"Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA carboxylase." Stadler S.C., Polanetz R., Meier S., Mayerhofer P.U., Herrmann J.M., Anslinger K., Roscher A.A., Roschinger W., Holzinger A. Biochem. Biophys. Res. Commun. 334:939-946(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 42-47, SUBCELLULAR LOCATION. Tissue: Kidney.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"Solution structure of RSGI RUH-072, an apo-biotinyl domain from human acetyl coenzyme A carboxylase." RIKEN structural genomics initiative (RSGI) Submitted (SEP-2007) to the PDB data bank Cited for: STRUCTURE BY NMR OF 640-725.
[11]	"Mutational spectrum in eight Korean patients with 3-methylcrotonyl-CoA carboxylase deficiency." Cho S.Y., Park H.D., Lee Y.W., Ki C.S., Lee S.Y., Sohn Y.B., Park S.W., Kim S.H., Ji S., Kim S.J., Choi E.W., Kim C.H., Ko A.R., Paik K.H., Lee D.H., Jin D.K. Clin. Genet. 81:96-98(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS MCC1D ARG-276 AND GLN-281.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF310972 mRNA. Translation: AAG53095.1.
AB029826 mRNA. Translation: BAA99407.1.
AF297332 mRNA. Translation: AAK67986.1.
AF310339 mRNA. Translation: AAG50245.1.
AK023051 mRNA. Translation: BAB14377.1.
AB209737 mRNA. Translation: BAD92974.1. Different initiation.
BC004214 mRNA. Translation: AAH04214.1.
BC004187 mRNA. Translation: AAH04187.1.

IPI

IPI00024580.

RefSeq

NP_064551.3. NM_020166.3.

UniGene

Hs.47649.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2EJM	NMR	-	A	640-725	[»]

ProteinModelPortal

Q96RQ3.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q96RQ3. 3 interactions.

STRING

9606.ENSP00000265594.

PTM databases

PhosphoSite

Q96RQ3.

Polymorphism databases

DMDM

108861983.

Proteomic databases

PaxDb

Q96RQ3.

PRIDE

Q96RQ3.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000265594; ENSP00000265594; ENSG00000078070.

GeneID

56922.

KEGG

hsa:56922.

UCSC

uc003fle.3. human.

Organism-specific databases

CTD

56922.

GeneCards

GC03M182733.

HGNC

HGNC:6936. MCCC1.

HPA

HPA008310.

MIM

210200. phenotype.
609010. gene.

neXtProt

NX_Q96RQ3.

Orphanet

6. Isolated 3-methylcrotonyl-CoA carboxylase deficiency.

PharmGKB

PA30680.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG4770.

HOGENOM

HOG000008989.

HOVERGEN

HBG000555.

InParanoid

Q96RQ3.

KO

K01968.

OMA

IEKFVDN.

OrthoDB

EOG4WQ123.

PhylomeDB

Q96RQ3.

Enzyme and pathway databases

BioCyc

MetaCyc:ENSG00000078070-MONOMER.

Reactome

REACT_111217. Metabolism.

UniPathway

UPA00363; UER00861.

Gene expression databases

ArrayExpress

Q96RQ3.

Bgee

Q96RQ3.

CleanEx

HS_MCCC1.

Genevestigator

Q96RQ3.

GermOnline

ENSG00000078070. Homo sapiens.

Family and domain databases

Gene3D

3.30.1490.20. 1 hit.
3.30.470.20. 1 hit.
3.40.50.20. 1 hit.

InterPro

IPR011761. ATP-grasp.
IPR013815. ATP_grasp_subdomain_1.
IPR013816. ATP_grasp_subdomain_2.
IPR001882. Biotin_BS.
IPR011764. Biotin_carboxylation_dom.
IPR005482. Biotin_COase_C.
IPR000089. Biotin_lipoyl.
IPR005481. CarbamoylP_synth_lsu_N.
IPR005479. CbamoylP_synth_lsu-like_ATP-bd.
IPR016185. PreATP-grasp_dom.
IPR011054. Rudment_hybrid_motif.
IPR011053. Single_hybrid_motif.
[Graphical view]

Pfam

PF02785. Biotin_carb_C. 1 hit.
PF00364. Biotin_lipoyl. 1 hit.
PF00289. CPSase_L_chain. 1 hit.
PF02786. CPSase_L_D2. 1 hit.
[Graphical view]

SMART

SM00878. Biotin_carb_C. 1 hit.
[Graphical view]

SUPFAM

SSF51230. Hybrid_motif. 1 hit.
SSF52440. PreATP-grasp-like. 1 hit.
SSF51246. Rudmnt_hyb_motif. 1 hit.

PROSITE

PS50975. ATP_GRASP. 1 hit.
PS50979. BC. 1 hit.
PS00188. BIOTIN. 1 hit.
PS50968. BIOTINYL_LIPOYL. 1 hit.
PS00867. CPSASE_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

MCCC1. human.

DrugBank

DB00121. Biotin.

EvolutionaryTrace

Q96RQ3.

GenomeRNAi

56922.

NextBio

62428.

SOURCE

Search...

Entry information

Entry name

MCCA_HUMAN

Accession

Primary (citable) accession number: Q96RQ3
Secondary accession number(s): Q59ES4, Q9H959, Q9NS97

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 5, 2002
Last sequence update:	May 30, 2006
Last modified:	May 1, 2013
This is version 134 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.