PDK4_MOUSE
ID PDK4_MOUSE Reviewed; 412 AA.
AC O70571;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1998, sequence version 1.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial;
DE EC=2.7.11.2;
DE AltName: Full=Pyruvate dehydrogenase kinase isoform 4;
DE Flags: Precursor;
GN Name=Pdk4;
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=C3H/HeJ; TISSUE=Heart;
RA Horiuchi M., Kobayashi K., Masuda M., Saheki T.;
RT "A novel gene in carnitine-deficient JVS mice.";
RL Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/SvJ;
RA Jeoung N.H., Bowker-Kinley M.M., Harris R.A.;
RT "Promoter and partial structural region of Mus musculus pyruvate
RT dehydrogenase kinase 4 (PDK4).";
RL Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Salivary gland;
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 [4]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=16606348; DOI=10.1042/bj20060125;
RA Jeoung N.H., Wu P., Joshi M.A., Jaskiewicz J., Bock C.B.,
RA Depaoli-Roach A.A., Harris R.A.;
RT "Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose
RT homoeostasis during starvation.";
RL Biochem. J. 397:417-425(2006).
RN [5]
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 [6]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=18430968; DOI=10.1152/ajpendo.00536.2007;
RA Jeoung N.H., Harris R.A.;
RT "Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and
RT improves glucose tolerance in diet-induced obese mice.";
RL Am. J. Physiol. 295:E46-E54(2008).
RN [7]
RP FUNCTION.
RX PubMed=18083902; DOI=10.1152/ajpheart.00870.2007;
RA Zhao G., Jeoung N.H., Burgess S.C., Rosaaen-Stowe K.A., Inagaki T.,
RA Latif S., Shelton J.M., McAnally J., Bassel-Duby R., Harris R.A.,
RA Richardson J.A., Kliewer S.A.;
RT "Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs
RT metabolism and exacerbates calcineurin-induced cardiomyopathy.";
RL Am. J. Physiol. 294:H936-H943(2008).
RN [8]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=19627255; DOI=10.1042/bj20090390;
RA Hwang B., Jeoung N.H., Harris R.A.;
RT "Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates
RT the long-term negative effects of a high-saturated fat diet.";
RL Biochem. J. 423:243-252(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, and Heart;
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 [10]
RP FUNCTION.
RX PubMed=21321124; DOI=10.1074/jbc.m110.217349;
RA Chambers K.T., Leone T.C., Sambandam N., Kovacs A., Wagg C.S.,
RA Lopaschuk G.D., Finck B.N., Kelly D.P.;
RT "Chronic inhibition of pyruvate dehydrogenase in heart triggers an adaptive
RT metabolic response.";
RL J. Biol. Chem. 286:11155-11162(2011).
RN [11]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
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).
RN [12]
RP DISRUPTION PHENOTYPE.
RX PubMed=21803180; DOI=10.1016/j.bone.2011.07.012;
RA Wang Y., Liu W., Masuyama R., Fukuyama R., Ito M., Zhang Q., Komori H.,
RA Murakami T., Moriishi T., Miyazaki T., Kitazawa R., Yoshida C.A., Kawai Y.,
RA Izumi S., Komori T.;
RT "Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by
RT promoting osteoclastogenesis.";
RL Bone 50:409-419(2012).
RN [13]
RP DISRUPTION PHENOTYPE.
RX PubMed=22436846; DOI=10.1093/cvr/cvs129;
RA Ussher J.R., Wang W., Gandhi M., Keung W., Samokhvalov V., Oka T.,
RA Wagg C.S., Jaswal J.S., Harris R.A., Clanachan A.S., Dyck J.R.,
RA Lopaschuk G.D.;
RT "Stimulation of glucose oxidation protects against acute myocardial
RT infarction and reperfusion injury.";
RL Cardiovasc. Res. 94:359-369(2012).
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. Inhibition
CC of pyruvate dehydrogenase decreases glucose utilization and increases
CC fat metabolism in response to prolonged fasting and starvation. Plays
CC an important role in maintaining normal blood glucose levels under
CC starvation, and is involved in the insulin signaling cascade. 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. In the fed state, mediates cellular
CC responses to glucose levels and to a high-fat diet. Regulates both
CC fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role
CC in the generation of reactive oxygen species. Protects detached
CC epithelial cells against anoikis. Plays a role in cell proliferation
CC via its role in regulating carbohydrate and fatty acid metabolism.
CC {ECO:0000269|PubMed:16606348, ECO:0000269|PubMed:18083902,
CC ECO:0000269|PubMed:18430968, ECO:0000269|PubMed:19627255,
CC ECO:0000269|PubMed:21321124, 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 -!- 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) (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000250}.
CC -!- INDUCTION: Up-regulated by PPARD. {ECO:0000269|PubMed:17669420}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype at birth. Mice have lower
CC blood glucose and pyruvate levels after overnight fasting than normal,
CC while the levels of ketone bodies are increased. After 48 h starving,
CC their rate of glucose oxidation is increased, and glycolysis decreased,
CC compared to wild type mice. Likewise, their rate of fatty acid
CC oxidation is lower than normal in response to starvation. In contrast,
CC there are no differences in blood glucose levels between fed mutant and
CC wild type mice. In response to a high-fat diet, mutant mice have lower
CC de novo fatty acid biosynthesis, and lower liver steatosis than wild-
CC type. Mutant mice show normal bone formation and normal bone
CC metabolism, excepting reduced bone loss when suspended to induce disuse
CC osteoporosis. {ECO:0000269|PubMed:16606348,
CC ECO:0000269|PubMed:18430968, ECO:0000269|PubMed:19627255,
CC ECO:0000269|PubMed:21803180, ECO:0000269|PubMed:22360721,
CC ECO:0000269|PubMed:22436846}.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
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DR EMBL; AJ001418; CAA04752.1; -; mRNA.
DR EMBL; AF239176; AAG44393.1; -; Genomic_DNA.
DR EMBL; BC026134; AAH26134.1; -; mRNA.
DR CCDS; CCDS19902.1; -.
DR RefSeq; NP_038771.1; NM_013743.2.
DR AlphaFoldDB; O70571; -.
DR SMR; O70571; -.
DR BioGRID; 205153; 5.
DR IntAct; O70571; 2.
DR STRING; 10090.ENSMUSP00000019721; -.
DR iPTMnet; O70571; -.
DR PhosphoSitePlus; O70571; -.
DR PaxDb; O70571; -.
DR PRIDE; O70571; -.
DR ProteomicsDB; 288084; -.
DR Antibodypedia; 15901; 637 antibodies from 36 providers.
DR DNASU; 27273; -.
DR Ensembl; ENSMUST00000019721; ENSMUSP00000019721; ENSMUSG00000019577.
DR GeneID; 27273; -.
DR KEGG; mmu:27273; -.
DR UCSC; uc009awk.1; mouse.
DR CTD; 5166; -.
DR MGI; MGI:1351481; Pdk4.
DR VEuPathDB; HostDB:ENSMUSG00000019577; -.
DR eggNOG; KOG0787; Eukaryota.
DR GeneTree; ENSGT01030000234646; -.
DR HOGENOM; CLU_023861_1_1_1; -.
DR InParanoid; O70571; -.
DR OMA; HQENCPS; -.
DR OrthoDB; 1242599at2759; -.
DR PhylomeDB; O70571; -.
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; 27273; 1 hit in 75 CRISPR screens.
DR ChiTaRS; Pdk4; mouse.
DR PRO; PR:O70571; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; O70571; protein.
DR Bgee; ENSMUSG00000019577; Expressed in hindlimb stylopod muscle and 211 other tissues.
DR ExpressionAtlas; O70571; baseline and differential.
DR Genevisible; O70571; MM.
DR GO; GO:0005743; C:mitochondrial inner membrane; HDA:MGI.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; TAS:MGI.
DR GO; GO:0004740; F:pyruvate dehydrogenase (acetyl-transferring) kinase activity; ISS:UniProtKB.
DR GO; GO:0071398; P:cellular response to fatty acid; ISS:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; ISS:UniProtKB.
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:2000811; P:negative regulation of anoikis; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; ISS:UniProtKB.
DR GO; GO:0010510; P:regulation of acetyl-CoA biosynthetic process from pyruvate; IMP:UniProtKB.
DR GO; GO:0045124; P:regulation of bone resorption; IMP:UniProtKB.
DR GO; GO:0010565; P:regulation of cellular ketone metabolic process; IMP:UniProtKB.
DR GO; GO:0042304; P:regulation of fatty acid biosynthetic process; IMP:UniProtKB.
DR GO; GO:0046320; P:regulation of fatty acid oxidation; 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 GO; GO:0042594; P:response to starvation; 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; Reference proteome; Transferase;
KW Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..412
FT /note="[Pyruvate dehydrogenase (acetyl-transferring)]
FT kinase isozyme 4, mitochondrial"
FT /id="PRO_0000023446"
FT DOMAIN 138..368
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT BINDING 254..261
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 293
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 312..313
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 329..334
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT SITE 157
FT /note="Interaction with the other subunit in the homodimer"
FT /evidence="ECO:0000250"
FT SITE 161
FT /note="Interaction with the other subunit in the homodimer"
FT /evidence="ECO:0000250"
FT SITE 395
FT /note="Interaction with the other subunit in the homodimer"
FT /evidence="ECO:0000250"
SQ SEQUENCE 412 AA; 46596 MW; 74815502E711054C CRC64;
MKAARFVMRS ASSLSSASLV PREVELFSRY SPSPLSMKQL LDFGSENACE RTSFAFLRQE
LPVRLANILK EIDILPDRLV NTPSVQLVKS WYIQSLMDLV EFHEKSPEDQ KALSEFVDTL
VKVRNRHHNV VPTMAQGILE YKDTCTVDPV TNQNLQYFLD RFYMNRISTR MLMNQHILIF
SDSKTGNPSH IGSIDPNCDV VAVVQDAFEC AKMLCDQYYL TSPELNLTQV NGKFPGQPIH
IVYVPSHLHH MLFELFKNAM RATVEHQENR PSLTPVEATV VLGKEDLTIK ISDRGGGVPL
RITDRLFSYT YSTAPTPVMD NSRNAPLAGF GYGLPISRLY AKYFQGDLNL YSMSGYGTDA
IIYLKALSSE SVEKLPVFNK SAFKHYQMSS EADDWCIPSR EPKNLAKEKL AV
