ID BCKD_HUMAN Reviewed; 412 AA.
AC O14874; A8MY43; Q6FGL4; Q96G95; Q96IN5;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 06-JUN-2002, sequence version 2.
DT 27-MAR-2024, entry version 208.
DE RecName: Full=Branched-chain alpha-ketoacid dehydrogenase kinase {ECO:0000303|PubMed:37558654};
DE Short=BCKDH kinase {ECO:0000303|PubMed:29779826};
DE Short=BCKDHKIN;
DE Short=BDK {ECO:0000303|PubMed:37558654};
DE EC=2.7.11.1 {ECO:0000269|PubMed:24449431, ECO:0000269|PubMed:29779826};
DE AltName: Full=[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial {ECO:0000305|PubMed:24449431};
DE EC=2.7.11.4 {ECO:0000269|PubMed:24449431, ECO:0000269|PubMed:29779826, ECO:0000269|PubMed:37558654};
DE Flags: Precursor;
GN Name=BCKDK {ECO:0000303|PubMed:29779826, ECO:0000312|HGNC:HGNC:16902};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Chuang J.C., Cox R.P., Chuang D.T.;
RL Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lung, and Placenta;
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 [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-192 AND LYS-233, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [13]
RP SUBUNIT.
RX PubMed=22589535; DOI=10.1074/jbc.m112.351031;
RA Zhou M., Lu G., Gao C., Wang Y., Sun H.;
RT "Tissue-specific and nutrient regulation of the branched-chain alpha-keto
RT acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm).";
RL J. Biol. Chem. 287:23397-23406(2012).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [15]
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., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [16]
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., Ayoub D.,
RA 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 [17]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=29779826; DOI=10.1016/j.cmet.2018.04.015;
RA White P.J., McGarrah R.W., Grimsrud P.A., Tso S.C., Yang W.H.,
RA Haldeman J.M., Grenier-Larouche T., An J., Lapworth A.L., Astapova I.,
RA Hannou S.A., George T., Arlotto M., Olson L.B., Lai M., Zhang G.F.,
RA Ilkayeva O., Herman M.A., Wynn R.M., Chuang D.T., Newgard C.B.;
RT "The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via
RT Regulation of ATP-Citrate Lyase.";
RL Cell Metab. 27:1281-1293.e7(2018).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.54 ANGSTROMS) OF 31-412 IN COMPLEX WITH ATP;
RP MG(2+) AND K(+), FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND
RP INTERACTION WITH DBT.
RX PubMed=37558654; DOI=10.1038/s41467-023-40536-y;
RA Roth Flach R.J., Bollinger E., Reyes A.R., Laforest B., Kormos B.L.,
RA Liu S., Reese M.R., Martinez Alsina L.A., Buzon L., Zhang Y., Bechle B.,
RA Rosado A., Sahasrabudhe P.V., Knafels J., Bhattacharya S.K., Omoto K.,
RA Stansfield J.C., Hurley L.D., Song L., Luo L., Breitkopf S.B., Monetti M.,
RA Cunio T., Tierney B., Geoly F.J., Delmore J., Siddall C.P., Xue L.,
RA Yip K.N., Kalgutkar A.S., Miller R.A., Zhang B.B., Filipski K.J.;
RT "Small molecule branched-chain ketoacid dehydrogenase kinase (BDK)
RT inhibitors with opposing effects on BDK protein levels.";
RL Nat. Commun. 14:4812-4812(2023).
RN [19]
RP VARIANT BCKDKD PRO-224.
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 [20]
RP VARIANTS BCKDKD GLY-174 AND PRO-389, CHARACTERIZATION OF VARIANTS BCKDKD
RP GLY-174 AND PRO-389, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION,
RP AUTOPHOSPHORYLATION, AND PATHWAY.
RX PubMed=24449431; DOI=10.1002/humu.22513;
RA Garcia-Cazorla A., Oyarzabal A., Fort J., Robles C., Castejon E.,
RA Ruiz-Sala P., Bodoy S., Merinero B., Lopez-Sala A., Dopazo J., Nunes V.,
RA Ugarte M., Artuch R., Palacin M., Rodriguez-Pombo P., Alcaide P.,
RA Navarrete R., Sanz P., Font-Llitjos M., Vilaseca M.A., Ormaizabal A.,
RA Pristoupilova A., Agullo S.B.;
RT "Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase
RT kinase) gene are responsible for a neurobehavioral deficit in two pediatric
RT unrelated patients.";
RL Hum. Mutat. 35:470-477(2014).
CC -!- FUNCTION: Serine/threonine-protein kinase component of macronutrients
CC metabolism. Forms a functional kinase and phosphatase pair with PPM1K,
CC serving as a metabolic regulatory node that coordinates branched-chain
CC amino acids (BCAAs) with glucose and lipid metabolism via two distinct
CC phosphoprotein targets: mitochondrial BCKDHA subunit of the branched-
CC chain alpha-ketoacid dehydrogenase (BCKDH) complex and cytosolic ACLY,
CC a lipogenic enzyme of Krebs cycle (PubMed:24449431, PubMed:29779826,
CC PubMed:37558654). Phosphorylates and inactivates mitochondrial BCKDH
CC complex a multisubunit complex consisting of three multimeric
CC components each involved in different steps of BCAA catabolism: E1
CC composed of BCKDHA and BCKDHB, E2 core composed of DBT monomers, and E3
CC composed of DLD monomers. Associates with the E2 component of BCKDH
CC complex and phosphorylates BCKDHA on Ser-337, leading to conformational
CC changes that interrupt substrate channeling between E1 and E2 and
CC inactivates the BCKDH complex (PubMed:29779826, PubMed:37558654).
CC Phosphorylates ACLY on Ser-455 in response to changes in cellular
CC carbohydrate abundance such as occurs during fasting to feeding
CC metabolic transition. Refeeding stimulates MLXIPL/ChREBP transcription
CC factor, leading to increased BCKDK to PPM1K expression ratio,
CC phosphorylation and activation of ACLY that ultimately results in the
CC generation of malonyl-CoA and oxaloacetate immediate substrates of de
CC novo lipogenesis and glucogenesis, respectively (PubMed:29779826).
CC Recognizes phosphosites having SxxE/D canonical motif
CC (PubMed:29779826). {ECO:0000269|PubMed:24449431,
CC ECO:0000269|PubMed:29779826, ECO:0000269|PubMed:37558654}.
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 Evidence={ECO:0000269|PubMed:24449431, ECO:0000269|PubMed:29779826,
CC ECO:0000269|PubMed:37558654};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17302;
CC Evidence={ECO:0000269|PubMed:24449431, ECO:0000269|PubMed:29779826,
CC ECO:0000269|PubMed:37558654};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:24449431, ECO:0000269|PubMed:29779826};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC Evidence={ECO:0000269|PubMed:24449431, ECO:0000269|PubMed:29779826};
CC -!- ACTIVITY REGULATION: Allosterically inhibited by certain thiazoles and
CC thiophenes: thiazoles increase interaction with DBT/BCKDH-E2, whereas
CC thiophenes reduce this interaction. Inhibited by
CC 3,6- dichlorobenzo[b]thiophene-2-carboxylic acid (BT2)
CC (PubMed:37558654). The ATP binding is mediated by both potassium and
CC magnesium ions (PubMed:37558654). {ECO:0000269|PubMed:37558654}.
CC -!- PATHWAY: Protein modification. {ECO:0000269|PubMed:24449431,
CC ECO:0000269|PubMed:29779826}.
CC -!- SUBUNIT: Homodimer. Homotetramer (By similarity). Dimerizes through
CC interaction of two opposing nucleotide-binding domains. Interacts with
CC E2 component of the branched-chain alpha-ketoacid dehydrogenase (BCKDH)
CC complex. Competes with BCKDK for binding to the E2 component; this
CC interaction is modulated by branched-chain alpha-keto acids. At steady
CC state, BCKDH holoenzyme contains BCKDK and BCKDHA is phosphorylated. In
CC response to high levels of branched-chain alpha-keto acids, the
CC inhibitory BCKDK is replaced by activating PPM1K leading to BCKDHA
CC dephosphorylation and BCAA degradation (PubMed:22589535,
CC PubMed:37558654). {ECO:0000250|UniProtKB:Q00972,
CC ECO:0000269|PubMed:22589535, ECO:0000269|PubMed:37558654}.
CC -!- INTERACTION:
CC O14874; P02549: SPTA1; NbExp=3; IntAct=EBI-1046765, EBI-375617;
CC O14874; P40763: STAT3; NbExp=2; IntAct=EBI-1046765, EBI-518675;
CC O14874; PRO_0000037548 [Q9WMX2]; Xeno; NbExp=2; IntAct=EBI-1046765, EBI-6863741;
CC O14874-2; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-25895587, EBI-2837444;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000250|UniProtKB:Q00972, ECO:0000305|PubMed:24449431}.
CC Note=Detected in the cytosolic compartment of liver cells.
CC {ECO:0000250|UniProtKB:Q00972}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O14874-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O14874-2; Sequence=VSP_054604, VSP_054605;
CC Name=3;
CC IsoId=O14874-3; Sequence=VSP_054605;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Autophosphorylated. {ECO:0000269|PubMed:24449431}.
CC -!- DISEASE: Branched-chain ketoacid dehydrogenase kinase deficiency
CC (BCKDKD) [MIM:614923]: A metabolic disorder characterized by autism,
CC epilepsy, intellectual disability, and reduced branched-chain amino
CC acids. {ECO:0000269|PubMed:22956686, ECO:0000269|PubMed:24449431}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry. A diet enriched in branched amino acids (BCAAs) allows
CC to normalize plasma BCAA levels. This suggests that it may be possible
CC to treat patients with mutations in BCKDK with BCAA supplementation.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The silence within - Issue
CC 147 of March 2013;
CC URL="https://web.expasy.org/spotlight/back_issues/147";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF026548; AAB82714.1; -; mRNA.
DR EMBL; AK130145; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; CR542093; CAG46890.1; -; mRNA.
DR EMBL; AC135050; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471192; EAW52160.1; -; Genomic_DNA.
DR EMBL; CH471192; EAW52161.1; -; Genomic_DNA.
DR EMBL; CH471192; EAW52163.1; -; Genomic_DNA.
DR EMBL; BC007363; AAH07363.1; -; mRNA.
DR EMBL; BC009872; AAH09872.1; -; mRNA.
DR CCDS; CCDS10705.1; -. [O14874-1]
DR CCDS; CCDS45467.1; -. [O14874-3]
DR CCDS; CCDS61917.1; -. [O14874-2]
DR RefSeq; NP_001116429.1; NM_001122957.2. [O14874-3]
DR RefSeq; NP_001258855.1; NM_001271926.1. [O14874-2]
DR RefSeq; NP_005872.2; NM_005881.3. [O14874-1]
DR PDB; 8F5F; X-ray; 3.15 A; A/B=31-412.
DR PDB; 8F5J; X-ray; 2.54 A; A=31-412.
DR PDB; 8F5S; X-ray; 2.79 A; A/B=31-412.
DR PDBsum; 8F5F; -.
DR PDBsum; 8F5J; -.
DR PDBsum; 8F5S; -.
DR AlphaFoldDB; O14874; -.
DR SMR; O14874; -.
DR BioGRID; 115583; 184.
DR IntAct; O14874; 66.
DR MINT; O14874; -.
DR STRING; 9606.ENSP00000378405; -.
DR BindingDB; O14874; -.
DR ChEMBL; CHEMBL4879410; -.
DR DrugBank; DB02930; Adenosine 5'-[gamma-thio]triphosphate.
DR GlyGen; O14874; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O14874; -.
DR PhosphoSitePlus; O14874; -.
DR SwissPalm; O14874; -.
DR BioMuta; BCKDK; -.
DR EPD; O14874; -.
DR jPOST; O14874; -.
DR MassIVE; O14874; -.
DR MaxQB; O14874; -.
DR PaxDb; 9606-ENSP00000378405; -.
DR PeptideAtlas; O14874; -.
DR ProteomicsDB; 2373; -.
DR ProteomicsDB; 48278; -. [O14874-1]
DR ProteomicsDB; 76605; -.
DR Pumba; O14874; -.
DR Antibodypedia; 13936; 389 antibodies from 30 providers.
DR DNASU; 10295; -.
DR Ensembl; ENST00000219794.11; ENSP00000219794.6; ENSG00000103507.14. [O14874-1]
DR Ensembl; ENST00000287507.7; ENSP00000287507.3; ENSG00000103507.14. [O14874-2]
DR Ensembl; ENST00000394950.7; ENSP00000378404.3; ENSG00000103507.14. [O14874-3]
DR Ensembl; ENST00000394951.5; ENSP00000378405.1; ENSG00000103507.14. [O14874-1]
DR GeneID; 10295; -.
DR KEGG; hsa:10295; -.
DR MANE-Select; ENST00000219794.11; ENSP00000219794.6; NM_005881.4; NP_005872.2.
DR UCSC; uc002eav.6; human. [O14874-1]
DR AGR; HGNC:16902; -.
DR CTD; 10295; -.
DR DisGeNET; 10295; -.
DR GeneCards; BCKDK; -.
DR HGNC; HGNC:16902; BCKDK.
DR HPA; ENSG00000103507; Low tissue specificity.
DR MalaCards; BCKDK; -.
DR MIM; 614901; gene.
DR MIM; 614923; phenotype.
DR neXtProt; NX_O14874; -.
DR OpenTargets; ENSG00000103507; -.
DR Orphanet; 308410; Autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency.
DR PharmGKB; PA134899581; -.
DR VEuPathDB; HostDB:ENSG00000103507; -.
DR eggNOG; KOG0787; Eukaryota.
DR GeneTree; ENSGT01030000234646; -.
DR HOGENOM; CLU_023861_4_0_1; -.
DR InParanoid; O14874; -.
DR OMA; WSYPPSA; -.
DR OrthoDB; 3058550at2759; -.
DR PhylomeDB; O14874; -.
DR TreeFam; TF331303; -.
DR PathwayCommons; O14874; -.
DR Reactome; R-HSA-70895; Branched-chain amino acid catabolism.
DR SignaLink; O14874; -.
DR SIGNOR; O14874; -.
DR BioGRID-ORCS; 10295; 13 hits in 1170 CRISPR screens.
DR ChiTaRS; BCKDK; human.
DR GeneWiki; BCKDK; -.
DR GenomeRNAi; 10295; -.
DR Pharos; O14874; Tbio.
DR PRO; PR:O14874; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; O14874; Protein.
DR Bgee; ENSG00000103507; Expressed in apex of heart and 172 other cell types or tissues.
DR ExpressionAtlas; O14874; baseline and differential.
DR Genevisible; O14874; HS.
DR GO; GO:0005947; C:mitochondrial alpha-ketoglutarate dehydrogenase complex; ISS:HGNC-UCL.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0047323; F:[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; ISS:HGNC-UCL.
DR GO; GO:0016301; F:kinase activity; TAS:HGNC-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:HGNC-UCL.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0004740; F:pyruvate dehydrogenase (acetyl-transferring) kinase activity; IBA:GO_Central.
DR GO; GO:0009063; P:amino acid catabolic process; NAS:UniProtKB.
DR GO; GO:0009083; P:branched-chain amino acid catabolic process; ISS:HGNC-UCL.
DR GO; GO:0008610; P:lipid biosynthetic process; IMP:UniProtKB.
DR GO; GO:0045763; P:negative regulation of cellular amino acid metabolic process; TAS:Reactome.
DR GO; GO:0016310; P:phosphorylation; ISS:HGNC-UCL.
DR GO; GO:0010906; P:regulation of glucose metabolic process; IBA:GO_Central.
DR CDD; cd16929; HATPase_PDK-like; 1.
DR Gene3D; 1.20.140.20; Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain; 1.
DR Gene3D; 3.30.565.10; Histidine kinase-like ATPase, C-terminal domain; 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:SF20; [3-METHYL-2-OXOBUTANOATE DEHYDROGENASE [LIPOAMIDE]] KINASE, MITOCHONDRIAL; 1.
DR PANTHER; PTHR11947; PYRUVATE DEHYDROGENASE KINASE; 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; SSF69012; alpha-ketoacid dehydrogenase kinase, N-terminal domain; 1.
DR SUPFAM; SSF55874; ATPase domain of HSP90 chaperone/DNA topoisomerase II/histidine kinase; 1.
DR PROSITE; PS50109; HIS_KIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Autism;
KW Autism spectrum disorder; Disease variant; Epilepsy;
KW Intellectual disability; 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="Branched-chain alpha-ketoacid dehydrogenase kinase"
FT /id="PRO_0000023452"
FT DOMAIN 159..404
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT BINDING 279
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J"
FT BINDING 279
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="structural"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J, ECO:0007744|PDB:8F5S"
FT BINDING 315
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J"
FT BINDING 328
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="structural"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J, ECO:0007744|PDB:8F5S"
FT BINDING 330
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="structural"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J, ECO:0007744|PDB:8F5S"
FT BINDING 333
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="structural"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J, ECO:0007744|PDB:8F5S"
FT BINDING 334
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J"
FT BINDING 335
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J"
FT BINDING 364
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J"
FT BINDING 367
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J"
FT BINDING 367
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="structural"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J, ECO:0007744|PDB:8F5S"
FT BINDING 370
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:37558654,
FT ECO:0007744|PDB:8F5J"
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:19608861"
FT MOD_RES 233
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 356
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O55028"
FT MOD_RES 360
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00972"
FT VAR_SEQ 282..311
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054604"
FT VAR_SEQ 366..412
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_054605"
FT VARIANT 174
FT /note="R -> G (in BCKDKD; partial loss of kinase activity)"
FT /evidence="ECO:0000269|PubMed:24449431"
FT /id="VAR_072184"
FT VARIANT 224
FT /note="R -> P (in BCKDKD; dbSNP:rs147210405)"
FT /evidence="ECO:0000269|PubMed:22956686"
FT /id="VAR_069037"
FT VARIANT 389
FT /note="L -> P (in BCKDKD; complete loss of kinase
FT activity)"
FT /evidence="ECO:0000269|PubMed:24449431"
FT /id="VAR_072185"
FT CONFLICT 3
FT /note="L -> P (in Ref. 2; AK130145)"
FT /evidence="ECO:0000305"
FT CONFLICT 114
FT /note="F -> S (in Ref. 2; AK130145)"
FT /evidence="ECO:0000305"
FT CONFLICT 218
FT /note="V -> F (in Ref. 1; AAB82714)"
FT /evidence="ECO:0000305"
FT CONFLICT 227
FT /note="P -> S (in Ref. 2; AK130145)"
FT /evidence="ECO:0000305"
FT HELIX 57..62
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 72..75
FT /evidence="ECO:0007829|PDB:8F5J"
FT TURN 81..83
FT /evidence="ECO:0007829|PDB:8F5F"
FT HELIX 85..110
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 114..117
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 120..138
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 145..161
FT /evidence="ECO:0007829|PDB:8F5J"
FT TURN 162..164
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 165..176
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 177..179
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 183..209
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 221..225
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 227..246
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 252..257
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 262..264
FT /evidence="ECO:0007829|PDB:8F5J"
FT HELIX 266..286
FT /evidence="ECO:0007829|PDB:8F5J"
FT TURN 287..290
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 291..294
FT /evidence="ECO:0007829|PDB:8F5S"
FT STRAND 298..304
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 306..315
FT /evidence="ECO:0007829|PDB:8F5J"
FT TURN 322..329
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 364..367
FT /evidence="ECO:0007829|PDB:8F5S"
FT HELIX 369..379
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 383..389
FT /evidence="ECO:0007829|PDB:8F5J"
FT TURN 390..392
FT /evidence="ECO:0007829|PDB:8F5J"
FT STRAND 393..401
FT /evidence="ECO:0007829|PDB:8F5J"
SQ SEQUENCE 412 AA; 46360 MW; AC97CF5D151FEFB4 CRC64;
MILASVLRSG PGGGLPLRPL LGPALALRAR STSATDTHHV EMARERSKTV TSFYNQSAID
AAAEKPSVRL TPTMMLYAGR SQDGSHLLKS ARYLQQELPV RIAHRIKGFR CLPFIIGCNP
TILHVHELYI RAFQKLTDFP PIKDQADEAQ YCQLVRQLLD DHKDVVTLLA EGLRESRKHI
EDEKLVRYFL DKTLTSRLGI RMLATHHLAL HEDKPDFVGI ICTRLSPKKI IEKWVDFARR
LCEHKYGNAP RVRINGHVAA RFPFIPMPLD YILPELLKNA MRATMESHLD TPYNVPDVVI
TIANNDVDLI IRISDRGGGI AHKDLDRVMD YHFTTAEAST QDPRISPLFG HLDMHSGAQS
GPMHGFGFGL PTSRAYAEYL GGSLQLQSLQ GIGTDVYLRL RHIDGREESF RI
//
