BCKD_MOUSE
ID BCKD_MOUSE Reviewed; 412 AA.
AC O55028;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial;
DE EC=2.7.11.4;
DE AltName: Full=Branched-chain alpha-ketoacid dehydrogenase kinase;
DE Short=BCKD-kinase;
DE Short=BCKDHKIN;
DE Flags: Precursor;
GN Name=Bckdk;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=9611264; DOI=10.1016/s0378-1119(98)00182-6;
RA Doering C.B., Coursey C., Spangler W., Danner D.J.;
RT "Murine branched chain alpha ketoacid dehydrogenase kinase; cDNA cloning,
RT tissue distribution, and temporal expression during embryonic
RT development.";
RL Gene 212:213-219(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Olfactory epithelium;
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 [3]
RP DISRUPTION PHENOTYPE.
RX PubMed=16875466; DOI=10.1042/bj20060869;
RA Joshi M.A., Jeoung N.H., Obayashi M., Hattab E.M., Brocken E.G.,
RA Liechty E.A., Kubek M.J., Vattem K.M., Wek R.C., Harris R.A.;
RT "Impaired growth and neurological abnormalities in branched-chain alpha-
RT keto acid dehydrogenase kinase-deficient mice.";
RL Biochem. J. 400:153-162(2006).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=16452087; DOI=10.1074/mcp.t500041-mcp200;
RA Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.;
RT "Comprehensive identification of phosphorylation sites in postsynaptic
RT density preparations.";
RL Mol. Cell. Proteomics 5:914-922(2006).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17208939; DOI=10.1074/mcp.m600218-mcp200;
RA Lee J., Xu Y., Chen Y., Sprung R., Kim S.C., Xie S., Zhao Y.;
RT "Mitochondrial phosphoproteome revealed by an improved IMAC method and
RT MS/MS/MS.";
RL Mol. Cell. Proteomics 6:669-676(2007).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Lung, Pancreas, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP DISRUPTION PHENOTYPE.
RX PubMed=22956686; DOI=10.1126/science.1224631;
RA Novarino G., El-Fishawy P., Kayserili H., Meguid N.A., Scott E.M.,
RA Schroth J., Silhavy J.L., Kara M., Khalil R.O., Ben-Omran T.,
RA Ercan-Sencicek A.G., Hashish A.F., Sanders S.J., Gupta A.R., Hashem H.S.,
RA Matern D., Gabriel S., Sweetman L., Rahimi Y., Harris R.A., State M.W.,
RA Gleeson J.G.;
RT "Mutations in BCKD-kinase lead to a potentially treatable form of autism
RT with epilepsy.";
RL Science 338:394-397(2012).
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-192, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23576753; DOI=10.1073/pnas.1302961110;
RA Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B.,
RA Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.;
RT "Label-free quantitative proteomics of the lysine acetylome in mitochondria
RT identifies substrates of SIRT3 in metabolic pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013).
CC -!- FUNCTION: Catalyzes the phosphorylation and inactivation of the
CC branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory
CC enzyme of the valine, leucine and isoleucine catabolic pathways. Key
CC enzyme that regulate the activity state of the BCKD complex.
CC {ECO:0000250|UniProtKB:O14874}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[3-methyl-2-oxobutanoate dehydrogenase] = ADP +
CC H(+) + O-phospho-L-seryl-[3-methyl-2-oxobutanoate dehydrogenase];
CC Xref=Rhea:RHEA:17301, Rhea:RHEA-COMP:13695, Rhea:RHEA-COMP:13696,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.4;
CC -!- SUBUNIT: Monomer. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix. Mitochondrion
CC {ECO:0000250|UniProtKB:O14874}.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- INDUCTION: Expression in female liver is influenced by circadian
CC rhythm.
CC -!- PTM: Autophosphorylated. {ECO:0000250|UniProtKB:O14874}.
CC -!- DISRUPTION PHENOTYPE: Mutant animals are born at the expected Mendelian
CC ratio, but they exhibit a decreased fertility. They are healthy at
CC birth. At 3 weeks of age, they start showing growth retardation. At 12
CC weeks, they are 15% smaller than their wild-type littermates. Adults
CC develop neurological abnormalities, such as tremors, epileptic seizures
CC and hindlimb clasping. These neurological deficits can be completely
CC abolished when mice are fed with a diet enriched in branched amino
CC acids. {ECO:0000269|PubMed:16875466, ECO:0000269|PubMed:22956686}.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
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DR EMBL; AF043070; AAB97689.1; -; mRNA.
DR EMBL; BC046595; AAH46595.1; -; mRNA.
DR CCDS; CCDS21884.1; -.
DR RefSeq; NP_033869.1; NM_009739.3.
DR AlphaFoldDB; O55028; -.
DR SMR; O55028; -.
DR BioGRID; 198316; 7.
DR STRING; 10090.ENSMUSP00000070345; -.
DR iPTMnet; O55028; -.
DR PhosphoSitePlus; O55028; -.
DR EPD; O55028; -.
DR jPOST; O55028; -.
DR PaxDb; O55028; -.
DR PeptideAtlas; O55028; -.
DR PRIDE; O55028; -.
DR ProteomicsDB; 273737; -.
DR Antibodypedia; 13936; 348 antibodies from 30 providers.
DR DNASU; 12041; -.
DR Ensembl; ENSMUST00000071056; ENSMUSP00000070345; ENSMUSG00000030802.
DR GeneID; 12041; -.
DR KEGG; mmu:12041; -.
DR UCSC; uc009jxf.1; mouse.
DR CTD; 10295; -.
DR MGI; MGI:1276121; Bckdk.
DR VEuPathDB; HostDB:ENSMUSG00000030802; -.
DR eggNOG; KOG0787; Eukaryota.
DR GeneTree; ENSGT01030000234646; -.
DR HOGENOM; CLU_023861_4_0_1; -.
DR InParanoid; O55028; -.
DR OMA; IHHLALH; -.
DR OrthoDB; 1242599at2759; -.
DR PhylomeDB; O55028; -.
DR TreeFam; TF331303; -.
DR BRENDA; 2.7.11.4; 3474.
DR Reactome; R-MMU-70895; Branched-chain amino acid catabolism.
DR BioGRID-ORCS; 12041; 2 hits in 75 CRISPR screens.
DR ChiTaRS; Bckdk; mouse.
DR PRO; PR:O55028; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; O55028; protein.
DR Bgee; ENSMUSG00000030802; Expressed in lacrimal gland and 263 other tissues.
DR ExpressionAtlas; O55028; baseline and differential.
DR Genevisible; O55028; MM.
DR GO; GO:0005947; C:mitochondrial alpha-ketoglutarate dehydrogenase complex; ISS:HGNC-UCL.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0047323; F:[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISS:HGNC-UCL.
DR GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:HGNC-UCL.
DR GO; GO:0004740; F:pyruvate dehydrogenase (acetyl-transferring) kinase activity; IBA:GO_Central.
DR GO; GO:0009083; P:branched-chain amino acid catabolic process; ISS:HGNC-UCL.
DR GO; GO:0006550; P:isoleucine catabolic process; ISO:MGI.
DR GO; GO:0006552; P:leucine catabolic process; ISO:MGI.
DR GO; GO:0016310; P:phosphorylation; ISS:HGNC-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0010906; P:regulation of glucose metabolic process; IBA:GO_Central.
DR GO; GO:0007283; P:spermatogenesis; ISO:MGI.
DR GO; GO:0006574; P:valine catabolic process; ISO:MGI.
DR Gene3D; 1.20.140.20; -; 1.
DR Gene3D; 3.30.565.10; -; 1.
DR InterPro; IPR036784; AK/P_DHK_N_sf.
DR InterPro; IPR018955; BCDHK/PDK_N.
DR InterPro; IPR039028; BCKD/PDK.
DR InterPro; IPR003594; HATPase_C.
DR InterPro; IPR036890; HATPase_C_sf.
DR InterPro; IPR005467; His_kinase_dom.
DR InterPro; IPR004358; Sig_transdc_His_kin-like_C.
DR PANTHER; PTHR11947; PTHR11947; 1.
DR Pfam; PF10436; BCDHK_Adom3; 1.
DR Pfam; PF02518; HATPase_c; 1.
DR PRINTS; PR00344; BCTRLSENSOR.
DR SMART; SM00387; HATPase_c; 1.
DR SUPFAM; SSF55874; SSF55874; 1.
DR SUPFAM; SSF69012; SSF69012; 1.
DR PROSITE; PS50109; HIS_KIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Kinase; Mitochondrion; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Transferase; Transit peptide.
FT TRANSIT 1..30
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 31..412
FT /note="[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]]
FT kinase, mitochondrial"
FT /id="PRO_0000023453"
FT DOMAIN 159..404
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT MOD_RES 31
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00972"
FT MOD_RES 52
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 192
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 233
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:O14874"
FT MOD_RES 356
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 360
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00972"
SQ SEQUENCE 412 AA; 46588 MW; 80B3B173AAC8AAD3 CRC64;
MILTSVLGSG PRSWSSLWPL LGSSLSLRAR STSATDTHHV ELARERSKTV TSFYNQSAID
VAAEKPSVRL TPTMMLYSGR SQDGSHLLKS GRYLQQELPV RIAHRIKGFR SLPFIIGCNP
TILHVHELYI RAFQKLTDFP PIKDQADEAQ YCQLVRQLLD DHKDVVTLLA EGLRESRKHI
QDEKLVRYFL DKTLTSRLGI RMLATHHLAL HEDKPDFVGI ICTRLSPKKI IEKWVDFARR
LCEHKYGNAP RVRINGHVAA RFPFIPMPLD YILPELLKNA MRATMESHLD TPYNVPDVVI
TIANNDIDLI IRISDRGGGI AHKDLDRVMD YHFTTAEAST QDPRINPLFG HLDMHSGGQS
GPMHGFGFGL PTSRAYAEYL GGSLQLQSLQ GIGTDVYLRL RHIDGREESF RI
