PDK2_MOUSE
ID PDK2_MOUSE Reviewed; 407 AA.
AC Q9JK42; Q8VC63;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial;
DE EC=2.7.11.2 {ECO:0000269|PubMed:22360721};
DE AltName: Full=Pyruvate dehydrogenase kinase isoform 2;
DE Short=PDH kinase 2;
DE Flags: Precursor;
GN Name=Pdk2;
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;
RA Jeoung N.H., Harris R.A.;
RT "Mus musculus pyruvate dehydrogenase kinase 2 cDNA.";
RL Submitted (MAY-2000) to the EMBL/GenBank/DDBJ databases.
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary tumor;
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 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 [6]
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 [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, and Pancreas;
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=21411764; DOI=10.1152/ajpregu.00498.2010;
RA Dunford E.C., Herbst E.A., Jeoung N.H., Gittings W., Inglis J.G.,
RA Vandenboom R., LeBlanc P.J., Harris R.A., Peters S.J.;
RT "PDH activation during in vitro muscle contractions in PDH kinase 2
RT knockout mice: effect of PDH kinase 1 compensation.";
RL Am. J. Physiol. 300:R1487-R1493(2011).
RN [9]
RP SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=21190881; DOI=10.1016/j.ymgme.2010.11.167;
RA Ushikai M., Horiuchi M., Kobayashi K., Matuda S., Inui A., Takeuchi T.,
RA Saheki T.;
RT "Induction of PDK4 in the heart muscle of JVS mice, an animal model of
RT systemic carnitine deficiency, does not appear to reduce glucose
RT utilization by the heart.";
RL Mol. Genet. Metab. 102:349-355(2011).
RN [10]
RP DISRUPTION PHENOTYPE, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=22360721; DOI=10.1042/bj20112197;
RA Jeoung N.H., Rahimi Y., Wu P., Lee W.N., Harris R.A.;
RT "Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-
RT knockout mice.";
RL Biochem. J. 443:829-839(2012).
CC -!- FUNCTION: Kinase that plays a key role in the regulation of glucose and
CC fatty acid metabolism and homeostasis via phosphorylation of the
CC pyruvate dehydrogenase subunits PDHA1 and PDHA2 (PubMed:22360721). This
CC inhibits pyruvate dehydrogenase activity, and thereby regulates
CC metabolite flux through the tricarboxylic acid cycle, down-regulates
CC aerobic respiration and inhibits the formation of acetyl-coenzyme A
CC from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose
CC utilization and increases fat metabolism. Mediates cellular responses
CC to insulin. Plays an important role in maintaining normal blood glucose
CC levels and in metabolic adaptation to nutrient availability. Via its
CC regulation of pyruvate dehydrogenase activity, plays an important role
CC in maintaining normal blood pH and in preventing the accumulation of
CC ketone bodies under starvation. Plays a role in the regulation of cell
CC proliferation and in resistance to apoptosis under oxidative stress.
CC Plays a role in p53/TP53-mediated apoptosis.
CC {ECO:0000269|PubMed:22360721}.
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:22360721};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23053;
CC Evidence={ECO:0000305|PubMed:22360721};
CC -!- SUBUNIT: Homodimer, and heterodimer with PDK1. 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).
CC {ECO:0000269|PubMed:21190881}.
CC -!- INTERACTION:
CC Q9JK42; O08908: Pik3r2; NbExp=3; IntAct=EBI-643530, EBI-643570;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:21190881}.
CC -!- TISSUE SPECIFICITY: Detected in heart (at protein level).
CC {ECO:0000269|PubMed:21190881}.
CC -!- INDUCTION: Up-regulated by glucose and palmitic acid. Up-regulated by
CC PPARD. {ECO:0000269|PubMed:16631612, ECO:0000269|PubMed:17669420}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype, due to the fact that PDK2-
CC deficient mice have increased PDK1 levels (PubMed:21411764). Mice have
CC lower blood glucose levels in the fed state, but not after fasting.
CC Likewise, they display increased pyruvate dehydrogenase activity in
CC liver and skeletal muscle in the fed state, but not after fasting.
CC Fasting mice lacking both PDK2 and PDK4 show strongly decreased blood
CC glucose levels, increased circulating ketone body levels leading to
CC ketoacidosis with dangerously low blood pH levels, hypothermia, and
CC ultimately death (PubMed:22360721). {ECO:0000269|PubMed:21411764,
CC ECO:0000269|PubMed:22360721}.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
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DR EMBL; AF267660; AAF72038.1; -; mRNA.
DR EMBL; AL606480; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466556; EDL15963.1; -; Genomic_DNA.
DR EMBL; BC021764; AAH21764.1; -; mRNA.
DR CCDS; CCDS25270.1; -.
DR RefSeq; NP_598428.2; NM_133667.2.
DR AlphaFoldDB; Q9JK42; -.
DR SMR; Q9JK42; -.
DR BioGRID; 202096; 12.
DR IntAct; Q9JK42; 3.
DR STRING; 10090.ENSMUSP00000041447; -.
DR iPTMnet; Q9JK42; -.
DR PhosphoSitePlus; Q9JK42; -.
DR EPD; Q9JK42; -.
DR jPOST; Q9JK42; -.
DR MaxQB; Q9JK42; -.
DR PaxDb; Q9JK42; -.
DR PeptideAtlas; Q9JK42; -.
DR PRIDE; Q9JK42; -.
DR ProteomicsDB; 294050; -.
DR Antibodypedia; 1630; 548 antibodies from 35 providers.
DR DNASU; 18604; -.
DR Ensembl; ENSMUST00000038431; ENSMUSP00000041447; ENSMUSG00000038967.
DR GeneID; 18604; -.
DR KEGG; mmu:18604; -.
DR UCSC; uc007kzu.2; mouse.
DR CTD; 5164; -.
DR MGI; MGI:1343087; Pdk2.
DR VEuPathDB; HostDB:ENSMUSG00000038967; -.
DR eggNOG; KOG0787; Eukaryota.
DR GeneTree; ENSGT01030000234646; -.
DR HOGENOM; CLU_023861_1_1_1; -.
DR InParanoid; Q9JK42; -.
DR OMA; APQIGDH; -.
DR OrthoDB; 1242599at2759; -.
DR PhylomeDB; Q9JK42; -.
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; 18604; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Pdk2; mouse.
DR PRO; PR:Q9JK42; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q9JK42; protein.
DR Bgee; ENSMUSG00000038967; Expressed in interventricular septum and 189 other tissues.
DR Genevisible; Q9JK42; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005967; C:mitochondrial pyruvate dehydrogenase complex; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO: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:0042803; F:protein homodimerization 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; IMP:UniProtKB.
DR GO; GO:0031670; P:cellular response to nutrient; IMP:UniProtKB.
DR GO; GO:0034614; P:cellular response to reactive oxygen species; ISO:MGI.
DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; ISO:MGI.
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:0050848; P:regulation of calcium-mediated signaling; IMP:MGI.
DR GO; GO:0010565; P:regulation of cellular ketone metabolic process; IMP:UniProtKB.
DR GO; GO:0006111; P:regulation of gluconeogenesis; IMP:UniProtKB.
DR GO; GO:0010906; P:regulation of glucose metabolic process; IMP:UniProtKB.
DR GO; GO:0006885; P:regulation of pH; 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 ATP-binding; Carbohydrate metabolism; Glucose metabolism; Kinase;
KW Mitochondrion; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Transferase; Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..407
FT /note="[Pyruvate dehydrogenase (acetyl-transferring)]
FT kinase isozyme 2, mitochondrial"
FT /id="PRO_0000023441"
FT DOMAIN 135..364
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT BINDING 251..258
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 290
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 309..310
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 325..330
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT MOD_RES 215
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 216
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 376
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8BFP9"
FT CONFLICT 299
FT /note="K -> R (in Ref. 1; AAF72038)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 407 AA; 46041 MW; DBB9F3F967C6A5B1 CRC64;
MRWVRALLKN ASLAGAPKYI EHFSKFSPSP LSMKQFLDFG SSNACEKTSF TFLRQELPVR
LANIMKEINL LPDRVLGTPS VQLVQSWYVQ SLLDIMEFLD KDPEDHRTLS QFTDALVTIR
NRHNDVVPTM AQGVLEYKDT YGDDPVSNQN IQYFLDRFYL SRISIRMLIN QHTLIFDGST
NPAHPKHIGS IDPNCSVSDV VKDAYDMAKL LCDKYYMASP DLEIQEVNAT NANQPIHMVY
VPSHLYHMLF ELFKNAMRAT VESHESSLTL PPIKIMVALG EEDLSIKMSD RGGGVPLRKI
ERLFSYMYST APTPQPGTGG TPLAGFGYGL PISRLYAKYF QGDLQLFSME GFGTDAVIYL
KALSTDSVER LPVYNKSAWR HYQTIQEAGD WCVPSTEPKN TSTYRVS
