O14874 (BCKD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial
EC=2.7.11.4

Alternative name(s):
Branched-chain alpha-ketoacid dehydrogenase kinase
Short name=BCKD-kinase
Short name=BCKDHKIN

Gene names

Name:

BCKDK

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	412 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)

Function	Catalyzes the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways. Key enzyme that regulate the activity state of the BCKD complex By similarity.
Catalytic activity	ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] = ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate.
Subunit structure	Monomer By similarity.
Subcellular location	Mitochondrion matrix.
Tissue specificity	Ubiquitous.
Post-translational modification	Autophosphorylated By similarity.
Involvement in disease	Branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) [MIM:614923]: A metabolic disorder characterized by autism, epilepsy, intellectual disability, and reduced branched-chain amino acids. Note: The disease is caused by mutations affecting the gene represented in this entry. A diet enriched in branched amino acids (BCAAs) allows to normalize plasma BCAA levels. This suggests that it may be possible to treat patients with mutations in BCKDK with BCAA supplementation. Ref.11
Sequence similarities	Belongs to the PDK/BCKDK protein kinase family. Contains 1 histidine kinase domain.

Ontologies

Keywords
Cellular component	Mitochondrion
Disease	Disease mutation
Domain	Transit peptide
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	branched-chain amino acid catabolic process Inferred from sequence or structural similarity. Source: HGNC
Cellular_component	mitochondrial alpha-ketoglutarate dehydrogenase complex Inferred from sequence or structural similarity. Source: HGNC
Molecular_function	ATP binding Inferred from sequence or structural similarity. Source: HGNC [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity Inferred from electronic annotation. Source: EC protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: HGNC
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
STAT3	P40763	2	EBI-1046765,EBI-518675

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 30	30	Mitochondrion By similarity
	Chain	31 – 412	382	[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial		PRO_0000023452
Regions
	Domain	159 – 404	246	Histidine kinase
Amino acid modifications
	Modified residue	31	1	Phosphoserine By similarity
	Modified residue	35	1	Phosphothreonine By similarity
	Modified residue	52	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	192	1	N6-acetyllysine Ref.8
	Modified residue	233	1	N6-acetyllysine Ref.8
Natural variations
	Natural variant	224	1	R → P in BCKDKD. Ref.11		VAR_069037
Experimental info
	Sequence conflict	218	1	V → F in AAB82714. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	O14874 [UniParc]. Last modified June 6, 2002. Version 2. Checksum: AC97CF5D151FEFB4	FASTA	412	46,360
	10 20 30 40 50 60 MILASVLRSG PGGGLPLRPL LGPALALRAR STSATDTHHV EMARERSKTV TSFYNQSAID 70 80 90 100 110 120 AAAEKPSVRL TPTMMLYAGR SQDGSHLLKS ARYLQQELPV RIAHRIKGFR CLPFIIGCNP 130 140 150 160 170 180 TILHVHELYI RAFQKLTDFP PIKDQADEAQ YCQLVRQLLD DHKDVVTLLA EGLRESRKHI 190 200 210 220 230 240 EDEKLVRYFL DKTLTSRLGI RMLATHHLAL HEDKPDFVGI ICTRLSPKKI IEKWVDFARR 250 260 270 280 290 300 LCEHKYGNAP RVRINGHVAA RFPFIPMPLD YILPELLKNA MRATMESHLD TPYNVPDVVI 310 320 330 340 350 360 TIANNDVDLI IRISDRGGGI AHKDLDRVMD YHFTTAEAST QDPRISPLFG HLDMHSGAQS 370 380 390 400 410 GPMHGFGFGL PTSRAYAEYL GGSLQLQSLQ GIGTDVYLRL RHIDGREESF RI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Chuang J.C., Cox R.P., Chuang D.T. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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]. Tissue: Placenta.
[5]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[6]	"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis." Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III J. Proteome Res. 7:1346-1351(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[7]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[8]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-192 AND LYS-233, MASS SPECTROMETRY.
[9]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[10]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy." Novarino G., El-Fishawy P., Kayserili H., Meguid N.A., Scott E.M., Schroth J., Silhavy J.L., Kara M., Khalil R.O., Ben-Omran T., Ercan-Sencicek A.G., Hashish A.F., Sanders S.J., Gupta A.R., Hashem H.S., Matern D., Gabriel S., Sweetman L. , Rahimi Y., Harris R.A., State M.W., Gleeson J.G. Science 338:394-397(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT BCKDKD PRO-224.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF026548 mRNA. Translation: AAB82714.1. CR542093 mRNA. Translation: CAG46890.1. CH471192 Genomic DNA. Translation: EAW52161.1. BC007363 mRNA. Translation: AAH07363.1.
IPI	IPI00298612.
RefSeq	NP_001116429.1. NM_001122957.2. NP_005872.2. NM_005881.3.
UniGene	Hs.513520.
3D structure databases
ProteinModelPortal	O14874.
ModBase	Search...
Protein-protein interaction databases
IntAct	O14874. 3 interactions.
MINT	MINT-2998419.
STRING	9606.ENSP00000219794.
PTM databases
PhosphoSite	O14874.
Proteomic databases
PaxDb	O14874.
PRIDE	O14874.
Protocols and materials databases
DNASU	10295.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000219794; ENSP00000219794; ENSG00000103507. ENST00000394951; ENSP00000378405; ENSG00000103507.
GeneID	10295.
KEGG	hsa:10295.
UCSC	uc002eav.4. human.
Organism-specific databases
CTD	10295.
GeneCards	GC16P031117.
HGNC	HGNC:16902. BCKDK.
HPA	HPA017995.
MIM	614901. gene. 614923. phenotype.
neXtProt	NX_O14874.
PharmGKB	PA134899581.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0642.
HOGENOM	HOG000164315.
HOVERGEN	HBG004829.
InParanoid	O14874.
KO	K00905.
OMA	HHLALHE.
OrthoDB	EOG49ZXPB.
PhylomeDB	O14874.
Gene expression databases
ArrayExpress	O14874.
Bgee	O14874.
CleanEx	HS_BCKDK.
Genevestigator	O14874.
GermOnline	ENSG00000103507. Homo sapiens.
Family and domain databases
Gene3D	1.20.140.20. 1 hit. 3.30.565.10. 1 hit.
InterPro	IPR018955. BCDHK/PDK_N. IPR003594. HATPase_ATP-bd. IPR004358. Sig_transdc_His_kin-like_C. IPR005467. Sig_transdc_His_kinase_core. [Graphical view]
Pfam	PF10436. BCDHK_Adom3. 1 hit. PF02518. HATPase_c. 1 hit. [Graphical view]
PRINTS	PR00344. BCTRLSENSOR.
SMART	SM00387. HATPase_c. 1 hit. [Graphical view]
SUPFAM	SSF55874. ATP_bd_ATPase. 1 hit. SSF69012. BCDHK/PDK_N. 1 hit.
PROSITE	PS50109. HIS_KIN. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	10295.
NextBio	39014.
SOURCE	Search...

Entry information

Entry name

BCKD_HUMAN

Accession

Primary (citable) accession number: O14874
Secondary accession number(s): Q6FGL4, Q96IN5

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	June 6, 2002
Last modified:	May 1, 2013
This is version 123 of the entry and version 2 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.