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Protein

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial

Gene

Pdk4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.6 Publications

Catalytic activityi

ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei293 – 2931ATPBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi254 – 2618ATPBy similarity
Nucleotide bindingi312 – 3132ATPBy similarity
Nucleotide bindingi329 – 3346ATPBy similarity

GO - Molecular functioni

GO - Biological processi

  • cellular response to fatty acid Source: UniProtKB
  • cellular response to starvation Source: UniProtKB
  • glucose homeostasis Source: UniProtKB
  • glucose metabolic process Source: UniProtKB-KW
  • insulin receptor signaling pathway Source: UniProtKB
  • negative regulation of anoikis Source: MGI
  • positive regulation of defense response to virus by host Source: MGI
  • reactive oxygen species metabolic process Source: UniProtKB
  • regulation of acetyl-CoA biosynthetic process from pyruvate Source: UniProtKB
  • regulation of bone resorption Source: UniProtKB
  • regulation of cellular ketone metabolic process Source: UniProtKB
  • regulation of fatty acid biosynthetic process Source: UniProtKB
  • regulation of fatty acid oxidation Source: UniProtKB
  • regulation of glucose metabolic process Source: UniProtKB
  • regulation of pH Source: UniProtKB
  • response to starvation Source: UniProtKB
  • xenophagy Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase

Keywords - Biological processi

Carbohydrate metabolism, Glucose metabolism

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-204174. Regulation of pyruvate dehydrogenase (PDH) complex.
R-MMU-5362517. Signaling by Retinoic Acid.

Names & Taxonomyi

Protein namesi
Recommended name:
[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial (EC:2.7.11.2)
Alternative name(s):
Pyruvate dehydrogenase kinase isoform 4
Gene namesi
Name:Pdk4
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 6

Organism-specific databases

MGIiMGI:1351481. Pdk4.

Subcellular locationi

GO - Cellular componenti

  • mitochondrial inner membrane Source: MGI
  • mitochondrial matrix Source: UniProtKB-SubCell
  • mitochondrion Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Disruption phenotypei

No visible phenotype at birth. Mice have lower blood glucose and pyruvate levels after overnight fasting than normal, while the levels of ketone bodies are increased. After 48 h starving, their rate of glucose oxidation is increased, and glycolysis decreased, compared to wild type mice. Likewise, their rate of fatty acid oxidation is lower than normal in response to starvation. In contrast, there are no differences in blood glucose levels betwen fed mutant and wild type mice. In response to a high-fat diet, mutant mice have lower de novo fatty acid biosynthesis, and lower liver steatosis than wild-type. Mutant mice show normal bone formation and normal bone metabolism, excepting reduced bone loss when suspended to induce disuse osteoporosis.6 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini? – 412[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrialPRO_0000023446
Transit peptidei1 – ?MitochondrionSequence analysis

Proteomic databases

PaxDbiO70571.
PRIDEiO70571.

PTM databases

iPTMnetiO70571.
PhosphoSiteiO70571.

Expressioni

Inductioni

Up-regulated by PPARD.1 Publication

Gene expression databases

BgeeiENSMUSG00000019577.
CleanExiMM_PDK4.
ExpressionAtlasiO70571. baseline and differential.
GenevisibleiO70571. MM.

Interactioni

Subunit structurei

Homodimer. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (By similarity).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei157 – 1571Interaction with the other subunit in the homodimerBy similarity
Sitei161 – 1611Interaction with the other subunit in the homodimerBy similarity
Sitei395 – 3951Interaction with the other subunit in the homodimerBy similarity

Protein-protein interaction databases

IntActiO70571. 1 interaction.
STRINGi10090.ENSMUSP00000019721.

Structurei

3D structure databases

ProteinModelPortaliO70571.
SMRiO70571. Positions 20-386.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini138 – 368231Histidine kinasePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Belongs to the PDK/BCKDK protein kinase family.Curated
Contains 1 histidine kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG0787. Eukaryota.
COG0642. LUCA.
HOGENOMiHOG000164315.
HOVERGENiHBG000511.
InParanoidiO70571.
KOiK00898.
OMAiPSREPKN.
OrthoDBiEOG091G07DJ.
PhylomeDBiO70571.
TreeFamiTF314918.

Family and domain databases

Gene3Di1.20.140.20. 1 hit.
3.30.565.10. 1 hit.
InterProiIPR018955. BCDHK/PDK_N.
IPR003594. HATPase_C.
IPR005467. His_kinase_dom.
[Graphical view]
PfamiPF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]
SMARTiSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMiSSF55874. SSF55874. 1 hit.
SSF69012. SSF69012. 1 hit.
PROSITEiPS50109. HIS_KIN. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

O70571-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKAARFVMRS ASSLSSASLV PREVELFSRY SPSPLSMKQL LDFGSENACE
60 70 80 90 100
RTSFAFLRQE LPVRLANILK EIDILPDRLV NTPSVQLVKS WYIQSLMDLV
110 120 130 140 150
EFHEKSPEDQ KALSEFVDTL VKVRNRHHNV VPTMAQGILE YKDTCTVDPV
160 170 180 190 200
TNQNLQYFLD RFYMNRISTR MLMNQHILIF SDSKTGNPSH IGSIDPNCDV
210 220 230 240 250
VAVVQDAFEC AKMLCDQYYL TSPELNLTQV NGKFPGQPIH IVYVPSHLHH
260 270 280 290 300
MLFELFKNAM RATVEHQENR PSLTPVEATV VLGKEDLTIK ISDRGGGVPL
310 320 330 340 350
RITDRLFSYT YSTAPTPVMD NSRNAPLAGF GYGLPISRLY AKYFQGDLNL
360 370 380 390 400
YSMSGYGTDA IIYLKALSSE SVEKLPVFNK SAFKHYQMSS EADDWCIPSR
410
EPKNLAKEKL AV
Length:412
Mass (Da):46,596
Last modified:August 1, 1998 - v1
Checksum:i74815502E711054C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ001418 mRNA. Translation: CAA04752.1.
AF239176 Genomic DNA. Translation: AAG44393.1.
BC026134 mRNA. Translation: AAH26134.1.
CCDSiCCDS19902.1.
RefSeqiNP_038771.1. NM_013743.2.
UniGeneiMm.235547.

Genome annotation databases

EnsembliENSMUST00000019721; ENSMUSP00000019721; ENSMUSG00000019577.
GeneIDi27273.
KEGGimmu:27273.
UCSCiuc009awk.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ001418 mRNA. Translation: CAA04752.1.
AF239176 Genomic DNA. Translation: AAG44393.1.
BC026134 mRNA. Translation: AAH26134.1.
CCDSiCCDS19902.1.
RefSeqiNP_038771.1. NM_013743.2.
UniGeneiMm.235547.

3D structure databases

ProteinModelPortaliO70571.
SMRiO70571. Positions 20-386.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiO70571. 1 interaction.
STRINGi10090.ENSMUSP00000019721.

PTM databases

iPTMnetiO70571.
PhosphoSiteiO70571.

Proteomic databases

PaxDbiO70571.
PRIDEiO70571.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000019721; ENSMUSP00000019721; ENSMUSG00000019577.
GeneIDi27273.
KEGGimmu:27273.
UCSCiuc009awk.1. mouse.

Organism-specific databases

CTDi5166.
MGIiMGI:1351481. Pdk4.

Phylogenomic databases

eggNOGiKOG0787. Eukaryota.
COG0642. LUCA.
HOGENOMiHOG000164315.
HOVERGENiHBG000511.
InParanoidiO70571.
KOiK00898.
OMAiPSREPKN.
OrthoDBiEOG091G07DJ.
PhylomeDBiO70571.
TreeFamiTF314918.

Enzyme and pathway databases

ReactomeiR-MMU-204174. Regulation of pyruvate dehydrogenase (PDH) complex.
R-MMU-5362517. Signaling by Retinoic Acid.

Miscellaneous databases

ChiTaRSiPdk4. mouse.
PROiO70571.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000019577.
CleanExiMM_PDK4.
ExpressionAtlasiO70571. baseline and differential.
GenevisibleiO70571. MM.

Family and domain databases

Gene3Di1.20.140.20. 1 hit.
3.30.565.10. 1 hit.
InterProiIPR018955. BCDHK/PDK_N.
IPR003594. HATPase_C.
IPR005467. His_kinase_dom.
[Graphical view]
PfamiPF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]
SMARTiSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMiSSF55874. SSF55874. 1 hit.
SSF69012. SSF69012. 1 hit.
PROSITEiPS50109. HIS_KIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiPDK4_MOUSE
AccessioniPrimary (citable) accession number: O70571
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: August 1, 1998
Last modified: September 7, 2016
This is version 135 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.