PDK4_RAT
ID PDK4_RAT Reviewed; 412 AA.
AC O54937;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 142.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=9405293; DOI=10.1042/bj3290191;
RA Bowker-Kinley M.M., Davis W.I., Wu P., Harris R.A., Popov K.M.;
RT "Evidence for existence of tissue-specific regulation of the mammalian
RT pyruvate dehydrogenase complex.";
RL Biochem. J. 329:191-196(1998).
RN [2]
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 [3]
RP INDUCTION BY EXERCISE; FASTING AND EPINEPHRINE.
RX PubMed=20739620; DOI=10.1152/ajpcell.00188.2010;
RA Wan Z., Thrush A.B., Legare M., Frier B.C., Sutherland L.N., Williams D.B.,
RA Wright D.C.;
RT "Epinephrine-mediated regulation of PDK4 mRNA in rat adipose tissue.";
RL Am. J. Physiol. 299:C1162-C1170(2010).
RN [4]
RP INDUCTION BY THYROID HORMONE.
RX PubMed=19948729; DOI=10.1074/jbc.m109.039081;
RA Attia R.R., Connnaughton S., Boone L.R., Wang F., Elam M.B., Ness G.C.,
RA Cook G.A., Park E.A.;
RT "Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone:
RT role of the peroxisome proliferator-activated receptor gamma coactivator
RT (PGC-1 alpha).";
RL J. Biol. Chem. 285:2375-2385(2010).
RN [5]
RP INDUCTION BY GLUCOCORTICOIDS AND INSULIN.
RX PubMed=19703515; DOI=10.1016/j.mce.2009.08.011;
RA Connaughton S., Chowdhury F., Attia R.R., Song S., Zhang Y., Elam M.B.,
RA Cook G.A., Park E.A.;
RT "Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene
RT expression by glucocorticoids and insulin.";
RL Mol. Cell. Endocrinol. 315:159-167(2010).
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:11486000}.
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:11486000, ECO:0000269|PubMed:9405293};
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.
CC -!- TISSUE SPECIFICITY: Ubiquitous; highest levels of expression in heart
CC and skeletal muscle. {ECO:0000269|PubMed:9405293}.
CC -!- INDUCTION: Up-regulated by exercise, starvation, glucocorticoids,
CC thyroid hormone and epinephrine. Down-regulated by insulin.
CC {ECO:0000269|PubMed:19703515, ECO:0000269|PubMed:19948729,
CC ECO:0000269|PubMed:20739620}.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
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DR EMBL; AF034577; AAC00177.1; -; mRNA.
DR RefSeq; NP_446003.1; NM_053551.1.
DR AlphaFoldDB; O54937; -.
DR SMR; O54937; -.
DR STRING; 10116.ENSRNOP00000012759; -.
DR BindingDB; O54937; -.
DR ChEMBL; CHEMBL2096663; -.
DR PhosphoSitePlus; O54937; -.
DR PaxDb; O54937; -.
DR PRIDE; O54937; -.
DR GeneID; 89813; -.
DR KEGG; rno:89813; -.
DR UCSC; RGD:69061; rat.
DR CTD; 5166; -.
DR RGD; 69061; Pdk4.
DR eggNOG; KOG0787; Eukaryota.
DR InParanoid; O54937; -.
DR OrthoDB; 1242599at2759; -.
DR PhylomeDB; O54937; -.
DR Reactome; R-RNO-204174; Regulation of pyruvate dehydrogenase (PDH) complex.
DR Reactome; R-RNO-5362517; Signaling by Retinoic Acid.
DR PRO; PR:O54937; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR GO; GO:0005524; F:ATP binding; IDA:RGD.
DR GO; GO:0004672; F:protein kinase activity; ISO:RGD.
DR GO; GO:0004740; F:pyruvate dehydrogenase (acetyl-transferring) kinase activity; IDA:UniProtKB.
DR GO; GO:0006086; P:acetyl-CoA biosynthetic process from pyruvate; TAS:RGD.
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; ISS:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:2000811; P:negative regulation of anoikis; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
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; ISS:UniProtKB.
DR GO; GO:0045124; P:regulation of bone resorption; ISO:RGD.
DR GO; GO:0010565; P:regulation of cellular ketone metabolic process; ISS:UniProtKB.
DR GO; GO:0042304; P:regulation of fatty acid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0046320; P:regulation of fatty acid oxidation; ISS:UniProtKB.
DR GO; GO:0010906; P:regulation of glucose metabolic process; ISS:UniProtKB.
DR GO; GO:0006885; P:regulation of pH; ISS:UniProtKB.
DR GO; GO:0042594; P:response to starvation; 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; 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_0000023447"
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; 46679 MW; 964A5DAAB189427A CRC64;
MKAARFVMRS ASSLGNAGLV PREVELFSRY SPSPLSMKQL LDFGSENACE RTSFSFLRQE
LPVRLANILK EIDILPEHLV NTPSVQLVKS WYIQSLMDLV EFHEKSPEDQ KVLSDFVDTL
VKVRNRHHNV VPTMAQGILE YKDNCTVDPV TNQNLQYFLD RFYMNRISTR MLMNQHILIF
SDSKTGNPSH IGSIDPNCDV VAVVEDAFEC AKMLCDQYYL TSPELKLTQV NGKFPGQPIH
IVYVPSHLHH MLFELFKNAM RATVEHQENR PFLTPVEATV VLGKEDLTIK ISDRGGGVPL
RITDRLFSYT YSTAPTPVMD NSRNAPLAGF GYGLPISRLY AKYFQGDLNL YSMSGYGTDA
IIYLKALSSE SIEKLPVFNK SAFKHYQMSS EADDWCIPSK EPKNLSKEKL AV
