Reviewed, UniProtKB/Swiss-Prot Q96RQ3 (MCCA_HUMAN)

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:carbon dioxide ligase subunit alpha
    3-methylcrotonyl-CoA carboxylase biotin-containing subunit

Gene names

Name:	MCCC1
Synonyms:	MCCA

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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.
Involvement in disease	Defects in MCCC1 are the cause of methylcrotonoyl-CoA carboxylase deficiency type 1 (MCC1 deficiency) [MIM:210200]. MCC1 deficiency is 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.
Sequence similarities	Contains 1 ATP-grasp domain. Contains 1 biotin carboxylation domain. Contains 1 biotinyl-binding domain.

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
Gene Ontology (GO)
Biological process	biotin metabolic process Ref.2 Non-traceable author statement. Source: UniProtKB leucine catabolic process Ref.1 Non-traceable author statement. Source: UniProtKB
Cellular component	Golgi apparatus Inferred from direct assay. Source: HPA mitochondrial matrix Ref.1 Non-traceable author statement. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW biotin binding Ref.2 Non-traceable author statement. Source: UniProtKB methylcrotonoyl-CoA carboxylase activity Ref.1 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 47

47

Mitochondrion Potential

Chain

48 – 725

678

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

289

1

A → V in MCC1 deficiency; mild form. Ref.4

VAR_012785

Natural variant

325

1

M → R in MCC1 deficiency. Ref.1

VAR_012786

Natural variant

385

1

R → S in MCC1 deficiency; severe form. dbSNP rs28934881. Ref.4 Ref.1

VAR_012787

Natural variant

437

1

L → P in MCC1 deficiency; severe form. dbSNP rs28934882. Ref.4

VAR_012788

Natural variant

464

1

H → P: dbSNP rs2270968. Ref.4 Ref.3 Ref.5 Ref.6 Ref.7

VAR_012789

Natural variant

532

1

D → H in MCC1 deficiency; severe form. Ref.4

VAR_012790

Natural variant

535

1

S → F in MCC1 deficiency; asymptomatic form. Ref.3

VAR_012791

Natural variant

560

1

N → T: dbSNP rs35219417.

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)
	Q96RQ3-1 [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: 11170888] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MCC1 DEFICIENCY 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: 11401427] [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: 11406611] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT MCC1 DEFICIENCY 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: 11181649] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MCC1 DEFICIENCY 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: 14702039] [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-464. Tissue: Skeletal muscle.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"Solution structure of 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.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.

UniGene

Hs.47649

3D structure databases

PDBPDBe

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

ModBase

Search...

Protein-protein interaction databases

STRING

Q96RQ3.

Proteomic databases

PRIDE

Q96RQ3.

Genome annotation databases

Ensembl

ENST00000265594; ENSP00000265594; ENSG00000078070; Homo sapiens. [Genome view]
ENST00000392616; ENSP00000376392; ENSG00000078070; Homo sapiens. [Genome view]
ENST00000448585; ENSP00000407708; ENSG00000078070; Homo sapiens. [Genome view]

GeneID

56922.

KEGG

hsa:56922.

NMPDR

fig|9606.3.peg.23558.

UCSC

uc003fle.1. human.

Organism-specific databases

CTD

56922.

GeneCards

GC03M184215.

HGNC

HGNC:6936. MCCC1.

HPA

HPA008310.

MIM

210200. phenotype.
609010. gene.

Orphanet

6. 3-methylcrotonylglycinuria.

PharmGKB

PA30680.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q96RQ3.

HOVERGEN

Q96RQ3.

OMA

VAPMTGT.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-10081.

BRENDA

6.4.1.4. 247.

Reactome

REACT_13. Metabolism of amino acids.

Gene expression databases

ArrayExpress

Q96RQ3.

Bgee

Q96RQ3.

CleanEx

HS_MCCC1.

Genevestigator

Q96RQ3.

GermOnline

ENSG00000078070. Homo sapiens.

Family and domain databases

InterPro

IPR011761. ATP-grasp.
IPR013816. ATP_grasp_subdomain_2.
IPR011764. BC.
IPR001882. Biotin_BS.
IPR005482. Biotin_COase_C.
IPR000089. Biotin_lipoyl.
IPR005479. CarbamoylP_synth_lsu_ATP-bd.
IPR005481. CarbamoylP_synth_lsu_N.
IPR013817. Pre-ATP_grasp.
[Graphical view]

Gene3D

G3DSA:3.30.470.20. ATP_grasp_subdomain_2. 1 hit.
G3DSA:3.40.50.20. Pre-ATP_grasp. 1 hit.

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]

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 Resources

DrugBank

DB00121. Biotin.

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:	November 3, 2009
This is version 99 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.