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Protein

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

Gene

PDK4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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.4 Publications

Catalytic activityi

ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei293ATP1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi254 – 261ATP1 Publication8
Nucleotide bindingi312 – 313ATP1 Publication2
Nucleotide bindingi329 – 334ATP1 Publication6

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • protein kinase activity Source: UniProtKB
  • pyruvate dehydrogenase (acetyl-transferring) kinase activity Source: Reactome

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: UniProtKB
  • reactive oxygen species metabolic process Source: UniProtKB
  • regulation of acetyl-CoA biosynthetic process from pyruvate Source: UniProtKB
  • regulation of bone resorption Source: Ensembl
  • 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

Keywordsi

Molecular functionKinase, Transferase
Biological processCarbohydrate metabolism, Glucose metabolism
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.2 2681
ReactomeiR-HSA-204174 Regulation of pyruvate dehydrogenase (PDH) complex
R-HSA-5362517 Signaling by Retinoic Acid
SIGNORiQ16654

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
Synonyms:PDHK4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 7

Organism-specific databases

EuPathDBiHostDB:ENSG00000004799.7
HGNCiHGNC:8812 PDK4
MIMi602527 gene
neXtProtiNX_Q16654

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi157Y → F: Loss of activity. 1 Publication1
Mutagenesisi161R → A: Loss of activity. 1 Publication1
Mutagenesisi394D → A: Loss of activity; when associated with A-395. 1 Publication1
Mutagenesisi395W → A: Loss of activity; when associated with A-394. 1 Publication1

Organism-specific databases

DisGeNETi5166
OpenTargetsiENSG00000004799
PharmGKBiPA33157

Chemistry databases

ChEMBLiCHEMBL4141
GuidetoPHARMACOLOGYi2144

Polymorphism and mutation databases

BioMutaiPDK4
DMDMi3183120

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_0000023445? – 411[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
Transit peptidei1 – ?MitochondrionSequence analysis

Proteomic databases

EPDiQ16654
PaxDbiQ16654
PeptideAtlasiQ16654
PRIDEiQ16654
ProteomicsDBi61013

PTM databases

iPTMnetiQ16654
PhosphoSitePlusiQ16654

Expressioni

Tissue specificityi

Ubiquitous; highest levels of expression in heart and skeletal muscle.2 Publications

Inductioni

Up-regulated by prolonged fasting, in glucose-deprived cells and in response to a high-fat diet. Down-regulated by insulin. Up-regulated by PPARD.5 Publications

Gene expression databases

BgeeiENSG00000004799
CleanExiHS_PDK4
ExpressionAtlasiQ16654 baseline and differential
GenevisibleiQ16654 HS

Organism-specific databases

HPAiHPA056731

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).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei157Interaction with the other subunit in the homodimer1
Sitei161Interaction with the other subunit in the homodimer1
Sitei395Interaction with the other subunit in the homodimer1

Protein-protein interaction databases

BioGridi111192, 5 interactors
IntActiQ16654, 3 interactors
STRINGi9606.ENSP00000005178

Chemistry databases

BindingDBiQ16654

Structurei

Secondary structure

1411
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi22 – 27Combined sources6
Helixi37 – 42Combined sources6
Helixi50 – 72Combined sources23
Helixi77 – 80Combined sources4
Helixi83 – 100Combined sources18
Beta strandi103 – 105Combined sources3
Helixi110 – 127Combined sources18
Helixi130 – 142Combined sources13
Turni149 – 151Combined sources3
Helixi153 – 180Combined sources28
Beta strandi194 – 199Combined sources6
Helixi200 – 219Combined sources20
Beta strandi225 – 234Combined sources10
Beta strandi240 – 243Combined sources4
Helixi245 – 266Combined sources22
Turni267 – 269Combined sources3
Beta strandi270 – 272Combined sources3
Beta strandi276 – 282Combined sources7
Beta strandi284 – 293Combined sources10
Helixi300 – 302Combined sources3
Helixi303 – 306Combined sources4
Beta strandi329 – 331Combined sources3
Helixi333 – 343Combined sources11
Beta strandi347 – 353Combined sources7
Turni354 – 356Combined sources3
Beta strandi357 – 367Combined sources11
Turni368 – 370Combined sources3
Helixi380 – 385Combined sources6

3D structure databases

ProteinModelPortaliQ16654
SMRiQ16654
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ16654

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini138 – 368Histidine kinasePROSITE-ProRule annotationAdd BLAST231

Sequence similaritiesi

Belongs to the PDK/BCKDK protein kinase family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG0787 Eukaryota
COG0642 LUCA
GeneTreeiENSGT00550000074574
HOGENOMiHOG000164315
HOVERGENiHBG000511
InParanoidiQ16654
KOiK00898
OMAiLMNQHIL
OrthoDBiEOG091G07DJ
PhylomeDBiQ16654
TreeFamiTF314918

Family and domain databases

CDDicd00075 HATPase_c, 1 hit
Gene3Di1.20.140.20, 1 hit
3.30.565.10, 1 hit
InterProiView protein in InterPro
IPR036784 AK/P_DHK_N_sf
IPR018955 BCDHK/PDK_N
IPR039028 BCKD/PDK
IPR003594 HATPase_C
IPR036890 HATPase_C_sf
IPR005467 His_kinase_dom
PANTHERiPTHR11947 PTHR11947, 1 hit
PfamiView protein in Pfam
PF10436 BCDHK_Adom3, 1 hit
PF02518 HATPase_c, 1 hit
SMARTiView protein in SMART
SM00387 HATPase_c, 1 hit
SUPFAMiSSF55874 SSF55874, 1 hit
SSF69012 SSF69012, 1 hit
PROSITEiView protein in PROSITE
PS50109 HIS_KIN, 1 hit

Sequencei

Sequence statusi: Complete.

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

Q16654-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKAARFVLRS AGSLNGAGLV PREVEHFSRY SPSPLSMKQL LDFGSENACE
60 70 80 90 100
RTSFAFLRQE LPVRLANILK EIDILPTQLV NTSSVQLVKS WYIQSLMDLV
110 120 130 140 150
EFHEKSPDDQ KALSDFVDTL IKVRNRHHNV VPTMAQGIIE YKDACTVDPV
160 170 180 190 200
TNQNLQYFLD RFYMNRISTR MLMNQHILIF SDSQTGNPSH IGSIDPNCDV
210 220 230 240 250
VAVVQDAFEC SRMLCDQYYL SSPELKLTQV NGKFPDQPIH IVYVPSHLHH
260 270 280 290 300
MLFELFKNAM RATVEHQENQ PSLTPIEVIV VLGKEDLTIK ISDRGGGVPL
310 320 330 340 350
RIIDRLFSYT YSTAPTPVMD NSRNAPLAGF GYGLPISRLY AKYFQGDLNL
360 370 380 390 400
YSLSGYGTDA IIYLKALSSE SIEKLPVFNK SAFKHYQMSS EADDWCIPSR
410
EPKNLAKEVA M
Length:411
Mass (Da):46,469
Last modified:November 1, 1996 - v1
Checksum:iC17B78B6057000E9
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04229817A → V1 PublicationCorresponds to variant dbSNP:rs56391840Ensembl.1
Natural variantiVAR_04229919L → M1 PublicationCorresponds to variant dbSNP:rs55761955Ensembl.1
Natural variantiVAR_042300109D → G1 PublicationCorresponds to variant dbSNP:rs34898343Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U54628
, U54618, U54619, U54620, U54621, U54622, U54623, U54624, U54625, U54626, U54627 Genomic DNA Translation: AAC50670.1
U54617 mRNA Translation: AAC50669.1
AC002451 Genomic DNA Translation: AAB67048.1
BC040239 mRNA Translation: AAH40239.1
CCDSiCCDS5643.1
RefSeqiNP_002603.1, NM_002612.3
UniGeneiHs.8364

Genome annotation databases

EnsembliENST00000005178; ENSP00000005178; ENSG00000004799
GeneIDi5166
KEGGihsa:5166
UCSCiuc003uoa.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiPDK4_HUMAN
AccessioniPrimary (citable) accession number: Q16654
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: July 18, 2018
This is version 169 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 7
    Human chromosome 7: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

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