PDK1_MOUSE
ID PDK1_MOUSE Reviewed; 434 AA.
AC Q8BFP9; Q3U5E5;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial;
DE EC=2.7.11.2;
DE AltName: Full=Pyruvate dehydrogenase kinase isoform 1;
DE Short=PDH kinase 1;
DE Flags: Precursor;
GN Name=Pdk1;
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 [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Medulla oblongata, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP INDUCTION BY PALMITATE AND GLUCOSE.
RX PubMed=16631612; DOI=10.1016/j.bbrc.2006.03.211;
RA Xu J., Han J., Epstein P.N., Liu Y.Q.;
RT "Regulation of PDK mRNA by high fatty acid and glucose in pancreatic
RT islets.";
RL Biochem. Biophys. Res. Commun. 344:827-833(2006).
RN [5]
RP INDUCTION BY HYPOXIA, AND FUNCTION.
RX PubMed=16517406; DOI=10.1016/j.cmet.2006.01.012;
RA Papandreou I., Cairns R.A., Fontana L., Lim A.L., Denko N.C.;
RT "HIF-1 mediates adaptation to hypoxia by actively downregulating
RT mitochondrial oxygen consumption.";
RL Cell Metab. 3:187-197(2006).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Pancreas, Spleen, and
RC Testis;
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 [7]
RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-403, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
CC -!- FUNCTION: Kinase that plays a key role in regulation of glucose and
CC fatty acid metabolism and homeostasis via phosphorylation of the
CC pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate
CC dehydrogenase activity, and thereby regulates metabolite flux through
CC the tricarboxylic acid cycle, down-regulates aerobic respiration and
CC inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an
CC important role in cellular responses to hypoxia and is important for
CC cell proliferation under hypoxia. Protects cells against apoptosis in
CC response to hypoxia and oxidative stress (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:16517406}.
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 -!- SUBUNIT: Homodimer, and heterodimer with PDK2. Interacts with the
CC pyruvate dehydrogenase complex subunit DLAT, and is part of the
CC multimeric pyruvate dehydrogenase complex that contains multiple copies
CC of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase
CC (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (By similarity).
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000250}.
CC -!- INDUCTION: Up-regulated by glucose and palmitate. Up- regulated via the
CC HIF1A signaling pathway in response to hypoxia.
CC {ECO:0000269|PubMed:16517406, ECO:0000269|PubMed:16631612}.
CC -!- PTM: Phosphorylated by constitutively activated ABL1, FGFR1, FLT3 and
CC JAK2 (in vitro), and this may also occur in cancer cells that express
CC constitutively activated ABL1, FGFR1, FLT3 and JAK2. Phosphorylation at
CC Tyr-241 and Tyr-242 strongly increases kinase activity, while
CC phosphorylation at Tyr-136 has a lesser effect (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
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DR EMBL; AK046805; BAC32879.1; -; mRNA.
DR EMBL; AK153649; BAE32134.1; -; mRNA.
DR EMBL; AL928963; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466519; EDL27100.1; -; Genomic_DNA.
DR EMBL; CH466519; EDL27102.1; -; Genomic_DNA.
DR EMBL; CH466519; EDL27104.1; -; Genomic_DNA.
DR CCDS; CCDS16119.1; -.
DR RefSeq; NP_766253.2; NM_172665.5.
DR AlphaFoldDB; Q8BFP9; -.
DR SMR; Q8BFP9; -.
DR BioGRID; 230707; 11.
DR STRING; 10090.ENSMUSP00000006669; -.
DR iPTMnet; Q8BFP9; -.
DR PhosphoSitePlus; Q8BFP9; -.
DR EPD; Q8BFP9; -.
DR jPOST; Q8BFP9; -.
DR MaxQB; Q8BFP9; -.
DR PaxDb; Q8BFP9; -.
DR PeptideAtlas; Q8BFP9; -.
DR PRIDE; Q8BFP9; -.
DR ProteomicsDB; 289336; -.
DR Antibodypedia; 4312; 692 antibodies from 40 providers.
DR DNASU; 228026; -.
DR Ensembl; ENSMUST00000006669; ENSMUSP00000006669; ENSMUSG00000006494.
DR GeneID; 228026; -.
DR KEGG; mmu:228026; -.
DR UCSC; uc008kbh.2; mouse.
DR CTD; 5163; -.
DR MGI; MGI:1926119; Pdk1.
DR VEuPathDB; HostDB:ENSMUSG00000006494; -.
DR eggNOG; KOG0787; Eukaryota.
DR GeneTree; ENSGT01030000234646; -.
DR HOGENOM; CLU_023861_1_1_1; -.
DR InParanoid; Q8BFP9; -.
DR OMA; TIKHYSN; -.
DR OrthoDB; 1242599at2759; -.
DR PhylomeDB; Q8BFP9; -.
DR TreeFam; TF314918; -.
DR BRENDA; 2.7.11.2; 3474.
DR Reactome; R-MMU-204174; Regulation of pyruvate dehydrogenase (PDH) complex.
DR Reactome; R-MMU-5362517; Signaling by Retinoic Acid.
DR BioGRID-ORCS; 228026; 0 hits in 77 CRISPR screens.
DR ChiTaRS; Pdk1; mouse.
DR PRO; PR:Q8BFP9; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q8BFP9; protein.
DR Bgee; ENSMUSG00000006494; Expressed in iris and 293 other tissues.
DR Genevisible; Q8BFP9; MM.
DR GO; GO:0005967; C:mitochondrial pyruvate dehydrogenase complex; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0005886; C:plasma membrane; ISA:MGI.
DR GO; GO:0045254; C:pyruvate dehydrogenase complex; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0004740; F:pyruvate dehydrogenase (acetyl-transferring) kinase activity; ISS:UniProtKB.
DR GO; GO:0008283; P:cell population proliferation; ISS:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; ISO:MGI.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0097411; P:hypoxia-inducible factor-1alpha signaling pathway; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; ISA:MGI.
DR GO; GO:0008631; P:intrinsic apoptotic signaling pathway in response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
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; ISS: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 ATP-binding; Carbohydrate metabolism; Glucose metabolism; Kinase;
KW Mitochondrion; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Transferase; Transit peptide.
FT TRANSIT 1..26
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 27..434
FT /note="[Pyruvate dehydrogenase (acetyl-transferring)]
FT kinase isozyme 1, mitochondrial"
FT /id="PRO_0000023438"
FT DOMAIN 161..391
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT BINDING 277..284
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 316
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 335..336
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 352..357
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT MOD_RES 136
FT /note="Phosphotyrosine; by FGFR1"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 241
FT /note="Phosphotyrosine; by FGFR1, ABL1, FLT3 and JAK2"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 242
FT /note="Phosphotyrosine; by FGFR1"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 403
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT CONFLICT 324
FT /note="R -> S (in Ref. 1; BAC32879)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 434 AA; 48995 MW; 8A514C863E751040 CRC64;
MRLARLLRGG TSVRPLCAVP CASRSLASAS ASGSGPASEL GVPGQVDFYA RFSPSPLSMK
QFLDFGSVNA CEKTSFMFLR QELPVRLANI MKEISLLPDN LLRTPSVQLV QSWYIQSLQE
LLDFKDKSAE DAKTIYEFTD TVIRIRNRHN DVIPTMAQGV TEYKESFGVD PVTSQNVQYF
LDRFYMSRIS IRMLLNQHSL LFGGKGSPSH RKHIGSINPN CDVVEVIKDG YENARRLCDL
YYVNSPELEL EELNAKSPGQ TIQVVYVPSH LYHMVFELFK NAMRATMEHH ADKGVYPPIQ
VHVTLGEEDL TVKMSDRGGG VPLRKIDRLF NYMYSTAPRP RVETSRAVPL AGFGYGLPIS
RLYAQYFQGD LKLYSLEGYG TDAVIYIKAL STESVERLPV YNKAAWKHYK ANHEADDWCV
PSREPKDMTT FRSS
