P10515 (ODP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial
EC=2.3.1.12

Alternative name(s):
70 kDa mitochondrial autoantigen of primary biliary cirrhosis
Short name=PBC
Dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex
M2 antigen complex 70 kDa subunit
Pyruvate dehydrogenase complex component E2
Short name=PDC-E2
Short name=PDCE2

Gene names

Name:	DLAT
Synonyms:	DLTA

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	647 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	The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2. It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3).
Catalytic activity	Acetyl-CoA + enzyme N(6)-(dihydrolipoyl)lysine = CoA + enzyme N(6)-(S-acetyldihydrolipoyl)lysine.
Cofactor	Binds 2 lipoyl cofactors covalently.
Subunit structure	20 to 30 alpha(2)-beta2 tetramers of E1 + 6 homodimers of E3 + 60 copies of E2. Interacts with PDK3.
Subcellular location	Mitochondrion matrix.
Involvement in disease	Note=Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex. Defects in DLAT are the cause of pyruvate dehydrogenase E2 deficiency (PDHE2 deficiency) [MIM:245348]; also known as lactic acidemia due to defect of E2 lipoyl transacetylase of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In this form of PDH deficiency episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent.
Sequence similarities	Belongs to the 2-oxoacid dehydrogenase family. Contains 2 lipoyl-binding domains.
Sequence caution	The sequence AAA62253.1 differs from that shown. Reason: Frameshift at positions 449, 451 and 455. The sequence AAA62253.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.

Ontologies

Keywords
Biological process	Glycolysis
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Domain	Lipoyl Repeat Transit peptide
Molecular function	Acyltransferase Transferase
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	glycolysis Inferred from electronic annotation. Source: UniProtKB-KW regulation of acetyl-CoA biosynthetic process from pyruvate Traceable author statement. Source: Reactome
Cellular component	mitochondrial pyruvate dehydrogenase complex Non-traceable author statement Ref.4. Source: UniProtKB
Molecular function	dihydrolipoyllysine-residue acetyltransferase activity Non-traceable author statement Ref.4. Source: UniProtKB protein binding Inferred from physical interaction Ref.9. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 86

86

Mitochondrion

Chain

87 – 647

561

Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial

PRO_0000020479

Regions

Domain

92 – 166

75

Lipoyl-binding 1

Domain

219 – 293

75

Lipoyl-binding 2

Region

358 – 389

32

E3-binding site By similarity

Region

417 – 647

231

Catalytic By similarity

Sites

Active site

620

1

Potential

Active site

624

1

Potential

Amino acid modifications

Modified residue

132

1

N6-lipoyllysine

Modified residue

259

1

N6-lipoyllysine

Modified residue

466

1

N6-acetyllysine Ref.5

Natural variations

Natural variant

43

1

A → V. Ref.1
Corresponds to variant rs2303436 [ dbSNP | Ensembl ].

VAR_047410

Natural variant

98

1

S → F.
Corresponds to variant rs537057 [ dbSNP | Ensembl ].

VAR_047411

Natural variant

99

1

L → F.
Corresponds to variant rs537060 [ dbSNP | Ensembl ].

VAR_047412

Natural variant

209

1

Q → R.
Corresponds to variant rs11553595 [ dbSNP | Ensembl ].

VAR_047413

Natural variant

313

1

D → V.
Corresponds to variant rs11553592 [ dbSNP | Ensembl ].

VAR_047414

Natural variant

318

1

V → A. Ref.1
Corresponds to variant rs627441 [ dbSNP | Ensembl ].

VAR_047415

Natural variant

451

1

D → N. Ref.1
Corresponds to variant rs10891314 [ dbSNP | Ensembl ].

VAR_047416

Experimental info

Sequence conflict

112

1

E → K in CAA68787. Ref.4

Sequence conflict

342

1

A → T in AAA62253. Ref.3

Sequence conflict

358

1

S → D in AAA62253. Ref.3

Secondary structure

1

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647

Helix Strand Turn

Details...

Beta strand

92 – 95

4

Beta strand

100 – 102

3

Beta strand

105 – 110

6

Beta strand

123 – 129

7

Beta strand

134 – 138

5

Beta strand

140 – 147

8

Beta strand

156 – 158

3

Beta strand

162 – 168

7

Helix

170 – 177

8

Beta strand

181 – 183

3

Beta strand

217 – 222

6

Beta strand

231 – 238

8

Beta strand

251 – 256

6

Beta strand

261 – 265

5

Beta strand

270 – 277

8

Beta strand

283 – 285

3

Beta strand

289 – 296

8

Helix

297 – 303

7

Sequences

	Sequence		Length	Mass (Da)
	P10515 [UniParc]. Last modified November 25, 2008. Version 3. Checksum: DD93A8E666E377C2	FASTA	647	68,997
	10 20 30 40 50 60 MWRVCARRAQ NVAPWAGLEA RWTALQEVPG TPRVTSRSGP APARRNSVTT GYGGVRALCG 70 80 90 100 110 120 WTPSSGATPR NRLLLQLLGS PGRRYYSLPP HQKVPLPSLS PTMQAGTIAR WEKKEGDKIN 130 140 150 160 170 180 EGDLIAEVET DKATVGFESL EECYMAKILV AEGTRDVPIG AIICITVGKP EDIEAFKNYT 190 200 210 220 230 240 LDSSAAPTPQ AAPAPTPAAT ASPPTPSAQA PGSSYPPHMQ VLLPALSPTM TMGTVQRWEK 250 260 270 280 290 300 KVGEKLSEGD LLAEIETDKA TIGFEVQEEG YLAKILVPEG TRDVPLGTPL CIIVEKEADI 310 320 330 340 350 360 SAFADYRPTE VTDLKPQVPP PTPPPVAAVP PTPQPLAPTP SAPCPATPAG PKGRVFVSPL 370 380 390 400 410 420 AKKLAVEKGI DLTQVKGTGP DGRITKKDID SFVPSKVAPA PAAVVPPTGP GMAPVPTGVF 430 440 450 460 470 480 TDIPISNIRR VIAQRLMQSK QTIPHYYLSI DVNMGEVLLV RKELNKILEG RSKISVNDFI 490 500 510 520 530 540 IKASALACLK VPEANSSWMD TVIRQNHVVD VSVAVSTPAG LITPIVFNAH IKGVETIAND 550 560 570 580 590 600 VVSLATKARE GKLQPHEFQG GTFTISNLGM FGIKNFSAII NPPQACILAI GASEDKLVPA 610 620 630 640 DNEKGFDVAS MMSVTLSCDH RVVDGAVGAQ WLAEFRKYLE KPITMLL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS VAL-43; ALA-318 AND ASN-451. Tissue: Kidney.
[2]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed: 16554811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase." Coppel R.L., McNeilage L.J., Surh C.D., van de Water J., Spithill T.W., Whittingham S., Gershwin M.E. Proc. Natl. Acad. Sci. U.S.A. 85:7317-7321(1988) [PubMed: 3174635] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 33-647. Tissue: Placenta.
[4]	"Nucleotide sequence of a cDNA for the dihydrolipoamide acetyltransferase component of human pyruvate dehydrogenase complex." Thekkumkara T.J., Ho L., Wexler I.D., Pon G., Liu T., Patel M.S. FEBS Lett. 240:45-48(1988) [PubMed: 3191998] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 73-647. Tissue: Liver.
[5]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-466, MASS SPECTROMETRY.
[6]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]	"Three-dimensional structure of the major autoantigen in primary biliary cirrhosis." Howard M.J., Fuller C., Broadhurst R.W., Perham R.N., Tang J.G., Quinn J., Diamond A.G., Yeaman S.J. Gastroenterology 115:139-146(1998) [PubMed: 9649469] [Abstract] Cited for: STRUCTURE BY NMR OF 214-315.
[8]	"Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency." Head R.A., Brown R.M., Zolkipli Z., Shahdadpuri R., King M.D., Clayton P.T., Brown G.K. Ann. Neurol. 58:234-241(2005) [PubMed: 16049940] [Abstract] Cited for: INVOLVEMENT IN PDHE2 DEFICIENCY.
[9]	"Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex." Kato M., Chuang J.L., Tso S.C., Wynn R.M., Chuang D.T. EMBO J. 24:1763-1774(2005) [PubMed: 15861126] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS) OF 212-319 IN COMPLEX WITH PDK3.
[10]	"Solution structure of RSGI RUH-058, a lipoyl domain of human 2-oxoacid dehydrogenase." RIKEN structural genomics initiative (RSGI) Submitted (OCT-2006) to the PDB data bank Cited for: STRUCTURE BY NMR OF 92-186.
[11]	"Crystal structure of an asymmetric complex of pyruvate dehydrogenase kinase 3 with lipoyl domain 2 and its biological implications." Devedjiev Y., Steussy C.N., Vassylyev D.G. J. Mol. Biol. 370:407-416(2007) [PubMed: 17532006] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 212-319 IN COMPLEX WITH PDK3.
[12]	"Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol." Kato M., Li J., Chuang J.L., Chuang D.T. Structure 15:992-1004(2007) [PubMed: 17683942] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 212-319 IN COMPLEX WITH PDK3.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AK223596 mRNA. Translation: BAD97316.1.
AP000907 Genomic DNA. No translation available.
J03866 mRNA. Translation: AAA62253.1. Sequence problems.
Y00978 mRNA. Translation: CAA68787.1.

IPI

IPI00021338.

PIR

A40497.

RefSeq

NP_001922.2. NM_001931.4.

UniGene

Hs.335551.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FYC	NMR	-	A	214-315	[»]
1Y8N	X-ray	2.60	B	212-319	[»]
1Y8O	X-ray	2.48	B	212-319	[»]
1Y8P	X-ray	2.63	B	212-319	[»]
2DNE	NMR	-	A	92-186	[»]
2PNR	X-ray	2.50	C/G	212-319	[»]
2Q8I	X-ray	2.60	B	212-319	[»]
3B8K	electron microscopy	8.80	A	409-647	[»]
3CRK	X-ray	2.30	C/D	214-300	[»]
3CRL	X-ray	2.61	C/D	214-300	[»]

ProteinModelPortal

P10515.

SMR

P10515. Positions 92-182, 214-315, 353-395, 409-647.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29496N.

IntAct

P10515. 5 interactions.

MINT

MINT-3007324.

STRING

P10515.

PTM databases

PhosphoSite

P10515.

Polymorphism databases

DMDM

215274207.

Proteomic databases

PRIDE

P10515.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000280346; ENSP00000280346; ENSG00000150768.

GeneID

1737.

KEGG

hsa:1737.

Organism-specific databases

CTD

1737.

GeneCards

GC11P111929.

H-InvDB

HIX0201624.

HGNC

HGNC:2896. DLAT.

HPA

CAB003782.

MIM

245348. phenotype.
608770. gene.

neXtProt

NX_P10515.

Orphanet

79244. Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex deficiency.

PharmGKB

PA27350.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG18935.

HOGENOM

HBG630916.

HOVERGEN

HBG005063.

InParanoid

P10515.

OMA

YASPMAK.

OrthoDB

EOG412M54.

PhylomeDB

P10515.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P10515.

Bgee

P10515.

CleanEx

HS_DLAT.

Genevestigator

P10515.

Family and domain databases

InterPro

IPR003016. 2-oxoA_DH_lipoyl-BS.
IPR001078. 2-oxoacid_DH_actylTfrase.
IPR006257. AcTrfase_Pyrv_DH_cplx_L.
IPR000089. Biotin_lipoyl.
IPR023213. CAT-like_dom.
IPR004167. E3-bd.
IPR011053. Single_hybrid_motif.
[Graphical view]

Gene3D

G3DSA:3.30.559.10. CAT-like_dom. 1 hit.
G3DSA:4.10.320.10. E3_bd. 1 hit.

KO

K00627.

Pfam

PF00198. 2-oxoacid_dh. 1 hit.
PF00364. Biotin_lipoyl. 2 hits.
PF02817. E3_binding. 1 hit.
[Graphical view]

SUPFAM

SSF47005. E3_bd. 1 hit.
SSF51230. Hybrid_motif. 2 hits.

TIGRFAMs

TIGR01349. PDHac_trf_mito. 1 hit.

PROSITE

PS50968. BIOTINYL_LIPOYL. 2 hits.
PS00189. LIPOYL. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00157. NADH.

SOURCE

Search...

Entry information

Entry name

ODP2_HUMAN

Accession

Primary (citable) accession number: P10515
Secondary accession number(s): Q16783, Q53EP3

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	November 25, 2008
Last modified:	January 25, 2012
This is version 152 of the entry and version 3 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.