Q16654 (PDK4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 4, mitochondrial
EC=2.7.11.2

Alternative name(s):
Pyruvate dehydrogenase kinase isoform 4

Gene names

Name:	PDK4
Synonyms:	PDHK4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	411 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.6 Ref.8 Ref.9
Catalytic activity	ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate. Ref.10
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.9 Ref.10
Subcellular location	Mitochondrion matrix.
Tissue specificity	Ubiquitous; highest levels of expression in heart and skeletal muscle. Ref.4 Ref.8
Induction	Up-regulated by prolonged fasting, in glucose-deprived cells and in response to a high-fat diet. Down-regulated by insulin. Ref.4 Ref.5 Ref.7 Ref.8 Ref.9
Sequence similarities	Belongs to the PDK/BCKDK protein kinase family. Contains 1 histidine kinase domain.

Ontologies

Keywords
Biological process	Carbohydrate metabolism Glucose metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Domain	Transit peptide
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular response to fatty acid Inferred from mutant phenotype Ref.7. 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.6. Source: UniProtKB negative regulation of anoikis Inferred from mutant phenotype Ref.6. Source: UniProtKB pyruvate metabolic process Traceable author statement. Source: Reactome reactive oxygen species metabolic process Inferred from mutant phenotype Ref.6. Source: UniProtKB regulation of acetyl-CoA biosynthetic process from pyruvate Inferred from mutant phenotype Ref.6. Source: UniProtKB regulation of fatty acid biosynthetic process Inferred from mutant phenotype Ref.6. 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.6. Source: UniProtKB regulation of pH Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	mitochondrial inner membrane Inferred from electronic annotation. Source: Compara mitochondrial matrix Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from direct assay Ref.9. 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – ?

Mitochondrion Potential

Chain

? – 411

[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 4, mitochondrial

PRO_0000023445

Regions

Domain

138 – 368

231

Histidine kinase

Nucleotide binding

254 – 261

8

ATP

Nucleotide binding

312 – 313

2

ATP

Nucleotide binding

329 – 334

6

ATP

Sites

Binding site

293

1

ATP

Site

157

1

Interaction with the other subunit in the homodimer

Site

161

1

Interaction with the other subunit in the homodimer

Site

395

1

Interaction with the other subunit in the homodimer

Natural variations

Natural variant

17

1

A → V. Ref.11
Corresponds to variant rs56391840 [ dbSNP | Ensembl ].

VAR_042298

Natural variant

19

1

L → M. Ref.11
Corresponds to variant rs55761955 [ dbSNP | Ensembl ].

VAR_042299

Natural variant

109

1

D → G. Ref.11
Corresponds to variant rs34898343 [ dbSNP | Ensembl ].

VAR_042300

Experimental info

Mutagenesis

157

1

Y → F: Loss of activity. Ref.9

Mutagenesis

161

1

R → A: Loss of activity. Ref.9

Mutagenesis

394

1

D → A: Loss of activity; when associated with A-395. Ref.9

Mutagenesis

395

1

W → A: Loss of activity; when associated with A-394. Ref.9

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

411

Helix Strand Turn

Details...

Helix

22 – 27

6

Helix

37 – 42

6

Helix

50 – 72

23

Helix

77 – 80

4

Helix

83 – 100

18

Beta strand

103 – 105

3

Helix

110 – 127

18

Helix

130 – 142

13

Turn

149 – 151

3

Helix

153 – 180

28

Beta strand

194 – 199

6

Helix

200 – 219

20

Beta strand

225 – 234

10

Beta strand

240 – 243

4

Helix

245 – 266

22

Turn

267 – 269

3

Beta strand

270 – 272

3

Beta strand

276 – 282

7

Beta strand

284 – 293

10

Helix

300 – 302

3

Helix

303 – 306

4

Beta strand

329 – 331

3

Helix

333 – 343

11

Beta strand

347 – 353

7

Turn

354 – 356

3

Beta strand

357 – 367

11

Turn

368 – 370

3

Helix

380 – 385

6

Sequences

	Sequence		Length	Mass (Da)
	Q16654 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: C17B78B6057000E9	FASTA	411	46,469
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"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.
[7]	"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.
[8]	"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.
[9]	"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.
[10]	"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.
[11]	"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. , 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 , 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.

IPI

IPI00003425.

RefSeq

NP_002603.1. NM_002612.3.

UniGene

Hs.8364.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2E0A	X-ray	1.86	A/B	20-411	[»]
2ZDX	X-ray	2.54	A/B	20-411	[»]
2ZDY	X-ray	2.40	A/B	20-411	[»]
2ZKJ	X-ray	2.00	A/B	20-411	[»]
3D2R	X-ray	2.03	A/B	20-411	[»]

ProteinModelPortal

Q16654.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q16654. 1 interaction.

STRING

9606.ENSP00000005178.

PTM databases

PhosphoSite

Q16654.

Polymorphism databases

DMDM

3183120.

Proteomic databases

PaxDb

Q16654.

PRIDE

Q16654.

Protocols and materials databases

DNASU

5166.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000005178; ENSP00000005178; ENSG00000004799.

GeneID

5166.

KEGG

hsa:5166.

UCSC

uc003uoa.3. human.

Organism-specific databases

CTD

5166.

GeneCards

GC07M095212.

HGNC

HGNC:8812. PDK4.

MIM

602527. gene.

neXtProt

NX_Q16654.

PharmGKB

PA33157.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0642.

HOGENOM

HOG000164315.

HOVERGEN

HBG000511.

InParanoid

Q16654.

KO

K00898.

OMA

SAFKHYQ.

OrthoDB

EOG4G1MGF.

PhylomeDB

Q16654.

Enzyme and pathway databases

BRENDA

2.7.11.2. 2681.

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

Q16654.

Bgee

Q16654.

CleanEx

HS_PDK4.

Genevestigator

Q16654.

GermOnline

ENSG00000004799. Homo sapiens.

Family and domain databases

Gene3D

1.20.140.20. 1 hit.
3.30.565.10. 1 hit.

InterPro

IPR018955. BCDHK/PDK_N.
IPR003594. HATPase_ATP-bd.
IPR005467. Sig_transdc_His_kinase_core.
[Graphical view]

Pfam

PF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]

SMART

SM00387. HATPase_c. 1 hit.
[Graphical view]

SUPFAM

SSF55874. ATP_bd_ATPase. 1 hit.
SSF69012. BCDHK/PDK_N. 1 hit.

PROSITE

PS50109. HIS_KIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q16654.

ChEMBL

CHEMBL4141.

ChiTaRS

PDK4. human.

EvolutionaryTrace

Q16654.

GenomeRNAi

5166.

NextBio

19986.

SOURCE

Search...

Entry information

Entry name

PDK4_HUMAN

Accession

Primary (citable) accession number: Q16654

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 126 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.