PDK3_HUMAN
ID PDK3_HUMAN Reviewed; 406 AA.
AC Q15120; B4DXG6;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 206.
DE RecName: Full=[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial;
DE EC=2.7.11.2;
DE AltName: Full=Pyruvate dehydrogenase kinase isoform 3;
DE Flags: Precursor;
GN Name=PDK3; Synonyms=PDHK3;
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).
RC TISSUE=Liver;
RX PubMed=7499431; DOI=10.1074/jbc.270.48.28989;
RA Gudi R., Bowker-Kinley M.M., Kedishvili N.Y., Zhao Y., Popov K.M.;
RT "Diversity of the pyruvate dehydrogenase kinase gene family in humans.";
RL J. Biol. Chem. 270:28989-28994(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
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 GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 [5]
RP CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH DLAT, AND ACTIVITY
RP REGULATION.
RX PubMed=10748134; DOI=10.1074/jbc.m909488199;
RA Baker J.C., Yan X., Peng T., Kasten S., Roche T.E.;
RT "Marked differences between two isoforms of human pyruvate dehydrogenase
RT kinase.";
RL J. Biol. Chem. 275:15773-15781(2000).
RN [6]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=11486000; DOI=10.1074/jbc.m103069200;
RA Korotchkina L.G., Patel M.S.;
RT "Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward
RT the three phosphorylation sites of human pyruvate dehydrogenase.";
RL J. Biol. Chem. 276:37223-37229(2001).
RN [7]
RP INTERACTION WITH DLAT.
RX PubMed=11978179; DOI=10.1042/bj20020301;
RA Tuganova A., Boulatnikov I., Popov K.M.;
RT "Interaction between the individual isoenzymes of pyruvate dehydrogenase
RT kinase and the inner lipoyl-bearing domain of transacetylase component of
RT pyruvate dehydrogenase complex.";
RL Biochem. J. 366:129-136(2002).
RN [8]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=16436377; DOI=10.1074/jbc.m511481200;
RA Korotchkina L.G., Sidhu S., Patel M.S.;
RT "Characterization of testis-specific isoenzyme of human pyruvate
RT dehydrogenase.";
RL J. Biol. Chem. 281:9688-9696(2006).
RN [9]
RP INDUCTION BY PPARD.
RX PubMed=17669420; DOI=10.1016/j.jmb.2007.06.091;
RA Degenhardt T., Saramaki A., Malinen M., Rieck M., Vaisanen S., Huotari A.,
RA Herzig K.H., Muller R., Carlberg C.;
RT "Three members of the human pyruvate dehydrogenase kinase gene family are
RT direct targets of the peroxisome proliferator-activated receptor
RT beta/delta.";
RL J. Mol. Biol. 372:341-355(2007).
RN [10]
RP FUNCTION, AND INDUCTION.
RX PubMed=18718909; DOI=10.1074/jbc.m803508200;
RA Lu C.W., Lin S.C., Chen K.F., Lai Y.Y., Tsai S.J.;
RT "Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1
RT promotes metabolic switch and drug resistance.";
RL J. Biol. Chem. 283:28106-28114(2008).
RN [11]
RP INDUCTION.
RX PubMed=20715114; DOI=10.1002/ijc.25599;
RA Blouin J.M., Penot G., Collinet M., Nacfer M., Forest C., Laurent-Puig P.,
RA Coumoul X., Barouki R., Benelli C., Bortoli S.;
RT "Butyrate elicits a metabolic switch in human colon cancer cells by
RT targeting the pyruvate dehydrogenase complex.";
RL Int. J. Cancer 128:2591-2601(2011).
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 FUNCTION.
RX PubMed=22865452; DOI=10.1158/0008-5472.can-12-0979;
RA Kluza J., Corazao-Rozas P., Touil Y., Jendoubi M., Maire C., Guerreschi P.,
RA Jonneaux A., Ballot C., Balayssac S., Valable S., Corroyer-Dulmont A.,
RA Bernaudin M., Malet-Martino M., de Lassalle E.M., Maboudou P.,
RA Formstecher P., Polakowska R., Mortier L., Marchetti P.;
RT "Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward
RT mitochondrial oxidative metabolism and potentiates the therapeutic activity
RT of pro-oxidants.";
RL Cancer Res. 72:5035-5047(2012).
RN [14]
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 [15]
RP X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS) OF 9-406 IN COMPLEX WITH ATP,
RP FUNCTION, AND INTERACTION WITH DLAT.
RX PubMed=15861126; DOI=10.1038/sj.emboj.7600663;
RA Kato M., Chuang J.L., Tso S.C., Wynn R.M., Chuang D.T.;
RT "Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl
RT domain 2 of human pyruvate dehydrogenase complex.";
RL EMBO J. 24:1763-1774(2005).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 9-406, AND INTERACTION WITH DLAT.
RX PubMed=17532006; DOI=10.1016/j.jmb.2007.04.083;
RA Devedjiev Y., Steussy C.N., Vassylyev D.G.;
RT "Crystal structure of an asymmetric complex of pyruvate dehydrogenase
RT kinase 3 with lipoyl domain 2 and its biological implications.";
RL J. Mol. Biol. 370:407-416(2007).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 9-406 IN COMPLEX WITH THE
RP INHIBITOR RADICICOL, FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH
RP DLAT.
RX PubMed=17683942; DOI=10.1016/j.str.2007.07.001;
RA Kato M., Li J., Chuang J.L., Chuang D.T.;
RT "Distinct structural mechanisms for inhibition of pyruvate dehydrogenase
RT kinase isoforms by AZD7545, dichloroacetate, and radicicol.";
RL Structure 15:992-1004(2007).
RN [18]
RP VARIANT [LARGE SCALE ANALYSIS] ALA-219.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [19]
RP VARIANT CMTX6 HIS-158, VARIANTS THR-114 AND SER-334, CHARACTERIZATION OF
RP VARIANT CMTX6 HIS-158, TISSUE SPECIFICITY, AND MUTAGENESIS OF ASN-120 AND
RP ASP-121.
RX PubMed=23297365; DOI=10.1093/hmg/dds557;
RA Kennerson M.L., Yiu E.M., Chuang D.T., Kidambi A., Tso S.C., Ly C.,
RA Chaudhry R., Drew A.P., Rance G., Delatycki M.B., Zuchner S., Ryan M.M.,
RA Nicholson G.A.;
RT "A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is
RT caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3)
RT gene.";
RL Hum. Mol. Genet. 22:1404-1416(2013).
CC -!- FUNCTION: Inhibits pyruvate dehydrogenase activity by phosphorylation
CC of the E1 subunit PDHA1, and thereby regulates glucose metabolism and
CC aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose
CC utilization and increases fat metabolism in response to prolonged
CC fasting, and as adaptation to a high-fat diet. Plays a role in glucose
CC homeostasis and in maintaining normal blood glucose levels in function
CC of nutrient levels and under starvation. Plays a role in the generation
CC of reactive oxygen species. {ECO:0000269|PubMed:10748134,
CC ECO:0000269|PubMed:11486000, ECO:0000269|PubMed:15861126,
CC ECO:0000269|PubMed:16436377, ECO:0000269|PubMed:17683942,
CC ECO:0000269|PubMed:18718909, ECO:0000269|PubMed:22865452}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[pyruvate dehydrogenase E1 alpha subunit] = ADP
CC + H(+) + O-phospho-L-seryl-[pyruvate dehydrogenase E1 alpha subunit];
CC Xref=Rhea:RHEA:23052, Rhea:RHEA-COMP:13689, Rhea:RHEA-COMP:13690,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.2;
CC Evidence={ECO:0000269|PubMed:10748134, ECO:0000269|PubMed:11486000,
CC ECO:0000269|PubMed:16436377};
CC -!- ACTIVITY REGULATION: Activated by interaction with DLAT. Inhibited by
CC AZD7545, dichloroacetate and radicicol. {ECO:0000269|PubMed:10748134,
CC ECO:0000269|PubMed:17683942}.
CC -!- SUBUNIT: Homodimer. Interacts with the pyruvate dehydrogenase complex
CC subunit DLAT, and is part of the multimeric pyruvate dehydrogenase
CC complex that contains multiple copies of pyruvate dehydrogenase (E1),
CC dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide
CC dehydrogenase (DLD, E3). {ECO:0000269|PubMed:10748134,
CC ECO:0000269|PubMed:11978179, ECO:0000269|PubMed:15861126,
CC ECO:0000269|PubMed:17532006, ECO:0000269|PubMed:17683942}.
CC -!- INTERACTION:
CC Q15120; P10515: DLAT; NbExp=2; IntAct=EBI-1383915, EBI-2959723;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q15120-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15120-2; Sequence=VSP_043365;
CC -!- TISSUE SPECIFICITY: Expressed in heart, skeletal muscle, spinal cord,
CC as well as fetal and adult brain. {ECO:0000269|PubMed:23297365}.
CC -!- INDUCTION: Up-regulated in response to hypoxia. Up-regulated in
CC response to fatty acids. Up-regulated by PPARD.
CC {ECO:0000269|PubMed:17669420, ECO:0000269|PubMed:18718909,
CC ECO:0000269|PubMed:20715114}.
CC -!- DISEASE: Charcot-Marie-Tooth disease, X-linked dominant, 6 (CMTX6)
CC [MIM:300905]: A form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness and
CC atrophy, initially of the peroneal muscles and later of the distal
CC muscles of the arms. Charcot-Marie-Tooth disease is classified in two
CC main groups on the basis of electrophysiologic properties and
CC histopathology: primary peripheral demyelinating neuropathies
CC characterized by severely reduced motor nerve conduction velocities
CC (NCVs) (less than 38m/s) and segmental demyelination and remyelination,
CC and primary peripheral axonal neuropathies characterized by normal or
CC mildly reduced NCVs and chronic axonal degeneration and regeneration on
CC nerve biopsy. {ECO:0000269|PubMed:23297365}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
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DR EMBL; L42452; AAC42011.1; -; mRNA.
DR EMBL; AK301965; BAG63378.1; -; mRNA.
DR EMBL; CH471074; EAW99019.1; -; Genomic_DNA.
DR EMBL; BC015948; AAH15948.1; -; mRNA.
DR CCDS; CCDS14212.1; -. [Q15120-1]
DR CCDS; CCDS48088.1; -. [Q15120-2]
DR PIR; I70160; I70160.
DR RefSeq; NP_001135858.1; NM_001142386.2. [Q15120-2]
DR RefSeq; NP_005382.1; NM_005391.4. [Q15120-1]
DR PDB; 1Y8N; X-ray; 2.60 A; A=9-406.
DR PDB; 1Y8O; X-ray; 2.48 A; A=9-406.
DR PDB; 1Y8P; X-ray; 2.63 A; A=9-406.
DR PDB; 2PNR; X-ray; 2.50 A; A/B/E/F=9-406.
DR PDB; 2Q8I; X-ray; 2.60 A; A=9-406.
DR PDBsum; 1Y8N; -.
DR PDBsum; 1Y8O; -.
DR PDBsum; 1Y8P; -.
DR PDBsum; 2PNR; -.
DR PDBsum; 2Q8I; -.
DR AlphaFoldDB; Q15120; -.
DR SMR; Q15120; -.
DR BioGRID; 111191; 107.
DR DIP; DIP-29498N; -.
DR IntAct; Q15120; 55.
DR MINT; Q15120; -.
DR STRING; 9606.ENSP00000387536; -.
DR BindingDB; Q15120; -.
DR ChEMBL; CHEMBL3893; -.
DR DrugBank; DB03760; Dihydrolipoic Acid.
DR DrugBank; DB03758; Radicicol.
DR DrugCentral; Q15120; -.
DR GuidetoPHARMACOLOGY; 2143; -.
DR iPTMnet; Q15120; -.
DR PhosphoSitePlus; Q15120; -.
DR BioMuta; PDK3; -.
DR DMDM; 3183119; -.
DR EPD; Q15120; -.
DR jPOST; Q15120; -.
DR MassIVE; Q15120; -.
DR MaxQB; Q15120; -.
DR PaxDb; Q15120; -.
DR PeptideAtlas; Q15120; -.
DR PRIDE; Q15120; -.
DR ProteomicsDB; 60447; -. [Q15120-1]
DR ProteomicsDB; 60448; -. [Q15120-2]
DR Antibodypedia; 24576; 320 antibodies from 30 providers.
DR DNASU; 5165; -.
DR Ensembl; ENST00000379162.9; ENSP00000368460.4; ENSG00000067992.17. [Q15120-1]
DR Ensembl; ENST00000568479.2; ENSP00000498864.1; ENSG00000067992.17. [Q15120-2]
DR Ensembl; ENST00000648777.1; ENSP00000497727.1; ENSG00000067992.17. [Q15120-1]
DR GeneID; 5165; -.
DR KEGG; hsa:5165; -.
DR MANE-Select; ENST00000379162.9; ENSP00000368460.4; NM_005391.5; NP_005382.1.
DR UCSC; uc004dbg.4; human. [Q15120-1]
DR CTD; 5165; -.
DR DisGeNET; 5165; -.
DR GeneCards; PDK3; -.
DR GeneReviews; PDK3; -.
DR HGNC; HGNC:8811; PDK3.
DR HPA; ENSG00000067992; Low tissue specificity.
DR MalaCards; PDK3; -.
DR MIM; 300905; phenotype.
DR MIM; 300906; gene.
DR neXtProt; NX_Q15120; -.
DR OpenTargets; ENSG00000067992; -.
DR Orphanet; 352675; X-linked Charcot-Marie-Tooth disease type 6.
DR PharmGKB; PA33156; -.
DR VEuPathDB; HostDB:ENSG00000067992; -.
DR eggNOG; KOG0787; Eukaryota.
DR GeneTree; ENSGT01030000234646; -.
DR HOGENOM; CLU_023861_1_1_1; -.
DR InParanoid; Q15120; -.
DR OMA; ITLNHIG; -.
DR OrthoDB; 1242599at2759; -.
DR PhylomeDB; Q15120; -.
DR TreeFam; TF314918; -.
DR BRENDA; 2.7.11.2; 2681.
DR PathwayCommons; Q15120; -.
DR Reactome; R-HSA-204174; Regulation of pyruvate dehydrogenase (PDH) complex.
DR Reactome; R-HSA-5362517; Signaling by Retinoic Acid.
DR SignaLink; Q15120; -.
DR SIGNOR; Q15120; -.
DR BioGRID-ORCS; 5165; 13 hits in 742 CRISPR screens.
DR ChiTaRS; PDK3; human.
DR EvolutionaryTrace; Q15120; -.
DR GeneWiki; PDK3; -.
DR GenomeRNAi; 5165; -.
DR Pharos; Q15120; Tchem.
DR PRO; PR:Q15120; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; Q15120; protein.
DR Bgee; ENSG00000067992; Expressed in middle temporal gyrus and 190 other tissues.
DR Genevisible; Q15120; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0004740; F:pyruvate dehydrogenase (acetyl-transferring) kinase activity; IDA:UniProtKB.
DR GO; GO:0071398; P:cellular response to fatty acid; IMP:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0097411; P:hypoxia-inducible factor-1alpha signaling pathway; IMP:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0035357; P:peroxisome proliferator activated receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0010510; P:regulation of acetyl-CoA biosynthetic process from pyruvate; IMP:UniProtKB.
DR GO; GO:0010906; P:regulation of glucose metabolic process; IMP:UniProtKB.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:UniProtKB.
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 PANTHER; PTHR11947; PTHR11947; 1.
DR Pfam; PF10436; BCDHK_Adom3; 1.
DR Pfam; PF02518; HATPase_c; 1.
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 3D-structure; Alternative splicing; ATP-binding; Carbohydrate metabolism;
KW Charcot-Marie-Tooth disease; Disease variant; Glucose metabolism; Kinase;
KW Mitochondrion; Neurodegeneration; Neuropathy; Nucleotide-binding;
KW Reference proteome; Transferase; Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..406
FT /note="[Pyruvate dehydrogenase (acetyl-transferring)]
FT kinase isozyme 3, mitochondrial"
FT /id="PRO_0000023443"
FT DOMAIN 131..362
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT REGION 383..406
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 247..254
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:15861126"
FT BINDING 287
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:15861126"
FT BINDING 306..307
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:15861126"
FT BINDING 323..328
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:15861126"
FT MOD_RES 278
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q922H2"
FT VAR_SEQ 406
FT /note="Q -> QDKIKTNRTF (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043365"
FT VARIANT 114
FT /note="K -> T (in dbSNP:rs146331370)"
FT /evidence="ECO:0000269|PubMed:23297365"
FT /id="VAR_070081"
FT VARIANT 158
FT /note="R -> H (in CMTX6; gain of function; results in a 5-
FT fold increase in kinase activity, decreased sensitivity to
FT pyruvate inhibition, reduced affinity for nucleotides and
FT increased affinity for pyruvate dehydrogenase complex
FT component E2 (PDC-E2), leading to PDC hyperphosphorylation
FT and increased inactivation; dbSNP:rs397515323)"
FT /evidence="ECO:0000269|PubMed:23297365"
FT /id="VAR_070082"
FT VARIANT 219
FT /note="E -> A (in a head & neck squamous cell carcinoma
FT sample; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042297"
FT VARIANT 334
FT /note="Y -> S"
FT /evidence="ECO:0000269|PubMed:23297365"
FT /id="VAR_070083"
FT MUTAGEN 120
FT /note="N->H: No effect on kinase activity; when associated
FT with N-121."
FT /evidence="ECO:0000269|PubMed:23297365"
FT MUTAGEN 121
FT /note="D->N: No effect on kinase activity; when associated
FT with H-120."
FT /evidence="ECO:0000269|PubMed:23297365"
FT HELIX 14..21
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 29..38
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 42..64
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 69..72
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 75..92
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 93..96
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 99..101
FT /evidence="ECO:0007829|PDB:2Q8I"
FT HELIX 102..118
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 119..121
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 122..137
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 141..172
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 179..184
FT /evidence="ECO:0007829|PDB:2PNR"
FT STRAND 187..192
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 193..212
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 218..224
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 233..236
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 238..260
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 262..265
FT /evidence="ECO:0007829|PDB:2PNR"
FT STRAND 270..276
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 278..287
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 294..297
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 298..301
FT /evidence="ECO:0007829|PDB:1Y8O"
FT TURN 303..305
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 323..325
FT /evidence="ECO:0007829|PDB:1Y8P"
FT HELIX 327..337
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 341..347
FT /evidence="ECO:0007829|PDB:1Y8O"
FT TURN 348..350
FT /evidence="ECO:0007829|PDB:1Y8O"
FT STRAND 351..360
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 362..364
FT /evidence="ECO:0007829|PDB:1Y8O"
FT HELIX 374..380
FT /evidence="ECO:0007829|PDB:1Y8O"
SQ SEQUENCE 406 AA; 46939 MW; EF2415D3F9D8D61E CRC64;
MRLFRWLLKQ PVPKQIERYS RFSPSPLSIK QFLDFGRDNA CEKTSYMFLR KELPVRLANT
MREVNLLPDN LLNRPSVGLV QSWYMQSFLE LLEYENKSPE DPQVLDNFLQ VLIKVRNRHN
DVVPTMAQGV IEYKEKFGFD PFISTNIQYF LDRFYTNRIS FRMLINQHTL LFGGDTNPVH
PKHIGSIDPT CNVADVVKDA YETAKMLCEQ YYLVAPELEV EEFNAKAPDK PIQVVYVPSH
LFHMLFELFK NSMRATVELY EDRKEGYPAV KTLVTLGKED LSIKISDLGG GVPLRKIDRL
FNYMYSTAPR PSLEPTRAAP LAGFGYGLPI SRLYARYFQG DLKLYSMEGV GTDAVIYLKA
LSSESFERLP VFNKSAWRHY KTTPEADDWS NPSSEPRDAS KYKAKQ
