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Q16654 (PDK4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 134. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial

EC=2.7.11.2
Alternative name(s):
Pyruvate dehydrogenase kinase isoform 4
Gene names
Name:PDK4
Synonyms:PDHK4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length411 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine 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. Ref.5 Ref.7 Ref.9 Ref.10

Catalytic activity

ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate. Ref.11

Subunit structure

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). Ref.10 Ref.11

Subcellular location

Mitochondrion matrix.

Tissue specificity

Ubiquitous; highest levels of expression in heart and skeletal muscle. Ref.4 Ref.9

Induction

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. Ref.4 Ref.5 Ref.6 Ref.8 Ref.9 Ref.10

Sequence similarities

Belongs to the PDK/BCKDK protein kinase family.

Contains 1 histidine kinase domain.

Ontologies

Keywords
   Biological processCarbohydrate metabolism
Glucose metabolism
   Cellular componentMitochondrion
   Coding sequence diversityPolymorphism
   DomainTransit peptide
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular metabolic process

Traceable author statement. Source: Reactome

cellular response to fatty acid

Inferred from mutant phenotype Ref.8. Source: UniProtKB

cellular response to starvation

Inferred from direct assay Ref.4. Source: UniProtKB

glucose homeostasis

Inferred from sequence or structural similarity. Source: UniProtKB

glucose metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

insulin receptor signaling pathway

Inferred from mutant phenotype Ref.7. Source: UniProtKB

negative regulation of anoikis

Inferred from mutant phenotype Ref.7. Source: UniProtKB

protein phosphorylation

Inferred from direct assay Ref.10. Source: GOC

pyruvate metabolic process

Traceable author statement. Source: Reactome

reactive oxygen species metabolic process

Inferred from mutant phenotype Ref.7. Source: UniProtKB

regulation of acetyl-CoA biosynthetic process from pyruvate

Inferred from mutant phenotype Ref.7. Source: UniProtKB

regulation of bone resorption

Inferred from electronic annotation. Source: Ensembl

regulation of cellular ketone metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of fatty acid biosynthetic process

Inferred from mutant phenotype Ref.7. Source: UniProtKB

regulation of fatty acid oxidation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of glucose metabolic process

Inferred from mutant phenotype Ref.7. Source: UniProtKB

regulation of pH

Inferred from sequence or structural similarity. Source: UniProtKB

response to starvation

Inferred from sequence or structural similarity. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentmitochondrial inner membrane

Inferred from electronic annotation. Source: Ensembl

mitochondrial matrix

Traceable author statement. Source: Reactome

mitochondrion

Traceable author statement Ref.1. Source: ProtInc

   Molecular_functionATP binding

Inferred from direct assay Ref.10. Source: UniProtKB

protein kinase activity

Inferred from direct assay Ref.10. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

pyruvate dehydrogenase (acetyl-transferring) kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – ?Mitochondrion Potential
Chain? – 411[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrialPRO_0000023445

Regions

Domain138 – 368231Histidine kinase
Nucleotide binding254 – 2618ATP
Nucleotide binding312 – 3132ATP
Nucleotide binding329 – 3346ATP

Sites

Binding site2931ATP
Site1571Interaction with the other subunit in the homodimer
Site1611Interaction with the other subunit in the homodimer
Site3951Interaction with the other subunit in the homodimer

Natural variations

Natural variant171A → V. Ref.12
Corresponds to variant rs56391840 [ dbSNP | Ensembl ].
VAR_042298
Natural variant191L → M. Ref.12
Corresponds to variant rs55761955 [ dbSNP | Ensembl ].
VAR_042299
Natural variant1091D → G. Ref.12
Corresponds to variant rs34898343 [ dbSNP | Ensembl ].
VAR_042300

Experimental info

Mutagenesis1571Y → F: Loss of activity. Ref.10
Mutagenesis1611R → A: Loss of activity. Ref.10
Mutagenesis3941D → A: Loss of activity; when associated with A-395. Ref.10
Mutagenesis3951W → A: Loss of activity; when associated with A-394. Ref.10

Secondary structure

.................................................. 411
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q16654 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: C17B78B6057000E9

FASTA41146,469
        10         20         30         40         50         60 
MKAARFVLRS AGSLNGAGLV PREVEHFSRY SPSPLSMKQL LDFGSENACE RTSFAFLRQE 

        70         80         90        100        110        120 
LPVRLANILK EIDILPTQLV NTSSVQLVKS WYIQSLMDLV EFHEKSPDDQ KALSDFVDTL 

       130        140        150        160        170        180 
IKVRNRHHNV VPTMAQGIIE YKDACTVDPV TNQNLQYFLD RFYMNRISTR MLMNQHILIF 

       190        200        210        220        230        240 
SDSQTGNPSH IGSIDPNCDV VAVVQDAFEC SRMLCDQYYL SSPELKLTQV NGKFPDQPIH 

       250        260        270        280        290        300 
IVYVPSHLHH MLFELFKNAM RATVEHQENQ PSLTPIEVIV VLGKEDLTIK ISDRGGGVPL 

       310        320        330        340        350        360 
RIIDRLFSYT YSTAPTPVMD NSRNAPLAGF GYGLPISRLY AKYFQGDLNL YSLSGYGTDA 

       370        380        390        400        410 
IIYLKALSSE SIEKLPVFNK SAFKHYQMSS EADDWCIPSR EPKNLAKEVA M 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human."
Rowles J., Scherer S.W., Xi T., Majer M., Nickle D.C., Rommens J.M., Popov K.M., Harris R.A., Riebow N.L., Xia J., Tsui L.-C., Bogardus C., Prochazka M.
J. Biol. Chem. 271:22376-22382(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]"The DNA sequence of human chromosome 7."
Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. expand/collapse author list , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K.
Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Cervix.
[4]"Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting."
Spriet L.L., Tunstall R.J., Watt M.J., Mehan K.A., Hargreaves M., Cameron-Smith D.
J. Appl. Physiol. 96:2082-2087(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, INDUCTION.
[5]"Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells."
Abbot E.L., McCormack J.G., Reynet C., Hassall D.G., Buchan K.W., Yeaman S.J.
FEBS J. 272:3004-3014(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
[6]"Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta."
Degenhardt T., Saramaki A., Malinen M., Rieck M., Vaisanen S., Huotari A., Herzig K.H., Muller R., Carlberg C.
J. Mol. Biol. 372:341-355(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION BY PPARD.
[7]"Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation."
Grassian A.R., Metallo C.M., Coloff J.L., Stephanopoulos G., Brugge J.S.
Genes Dev. 25:1716-1733(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex."
Blouin J.M., Penot G., Collinet M., Nacfer M., Forest C., Laurent-Puig P., Coumoul X., Barouki R., Benelli C., Bortoli S.
Int. J. Cancer 128:2591-2601(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[9]"Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus."
Kulkarni S.S., Salehzadeh F., Fritz T., Zierath J.R., Krook A., Osler M.E.
Metabolism 61:175-185(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION, TISSUE SPECIFICITY.
[10]"Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity."
Wynn R.M., Kato M., Chuang J.L., Tso S.C., Li J., Chuang D.T.
J. Biol. Chem. 283:25305-25315(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 20-411 IN COMPLEX WITH ATP, FUNCTION, ENZYME REGULATION, SUBUNIT, MUTAGENESIS OF TYR-157; ARG-161; ASP-394 AND TRP-395.
[11]"Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4."
Kukimoto-Niino M., Tokmakov A., Terada T., Ohbayashi N., Fujimoto T., Gomi S., Shiromizu I., Kawamoto M., Matsusue T., Shirouzu M., Yokoyama S.
Acta Crystallogr. D 67:763-773(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 20-411 IN COMPLEX WITH ATP ANALOG, CATALYTIC ACTIVITY, SUBUNIT.
[12]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-17; MET-19 AND GLY-109.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U54628 expand/collapse EMBL AC list , 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.
RefSeqNP_002603.1. NM_002612.3.
UniGeneHs.8364.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2E0AX-ray1.86A/B20-411[»]
2ZDXX-ray2.54A/B20-411[»]
2ZDYX-ray2.40A/B20-411[»]
2ZKJX-ray2.00A/B20-411[»]
3D2RX-ray2.03A/B20-411[»]
ProteinModelPortalQ16654.
SMRQ16654. Positions 20-386.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111192. 2 interactions.
IntActQ16654. 1 interaction.
STRING9606.ENSP00000005178.

Chemistry

BindingDBQ16654.
ChEMBLCHEMBL4141.

PTM databases

PhosphoSiteQ16654.

Polymorphism databases

DMDM3183120.

Proteomic databases

PaxDbQ16654.
PRIDEQ16654.

Protocols and materials databases

DNASU5166.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000005178; ENSP00000005178; ENSG00000004799.
GeneID5166.
KEGGhsa:5166.
UCSCuc003uoa.3. human.

Organism-specific databases

CTD5166.
GeneCardsGC07M095212.
HGNCHGNC:8812. PDK4.
HPAHPA056731.
MIM602527. gene.
neXtProtNX_Q16654.
PharmGKBPA33157.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0642.
HOGENOMHOG000164315.
HOVERGENHBG000511.
InParanoidQ16654.
KOK00898.
OMAPSREPKN.
OrthoDBEOG71VSSV.
PhylomeDBQ16654.
TreeFamTF314918.

Enzyme and pathway databases

BRENDA2.7.11.2. 2681.
ReactomeREACT_111217. Metabolism.

Gene expression databases

ArrayExpressQ16654.
BgeeQ16654.
CleanExHS_PDK4.
GenevestigatorQ16654.

Family and domain databases

Gene3D1.20.140.20. 1 hit.
3.30.565.10. 1 hit.
InterProIPR018955. BCDHK/PDK_N.
IPR003594. HATPase_ATP-bd.
IPR005467. Sig_transdc_His_kinase_core.
[Graphical view]
PfamPF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]
SMARTSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMSSF55874. SSF55874. 1 hit.
SSF69012. SSF69012. 1 hit.
PROSITEPS50109. HIS_KIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSPDK4. human.
EvolutionaryTraceQ16654.
GeneWikiPDK4.
GenomeRNAi5166.
NextBio19986.
PROQ16654.
SOURCESearch...

Entry information

Entry namePDK4_HUMAN
AccessionPrimary (citable) accession number: Q16654
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 134 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 7

Human chromosome 7: entries, gene names and cross-references to MIM