Q96Q83 (ALKB3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3
EC=1.14.11.-

Alternative name(s):
Alkylated DNA repair protein alkB homolog 3
DEPC-1
Prostate cancer antigen 1

Gene names

Name:	ALKBH3
Synonyms:	ABH3, DEPC1

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	286 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Dioxygenase that repairs alkylated DNA containing 1-methyladenine (1meA) and 3-methylcytosine (3meC) by oxidative demethylation. Has a strong preference for single-stranded DNA. Able to process alkylated 3mC within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKHB3. May also act on RNA. Requires molecular oxygen, alpha-ketoglutarate and iron. Ref.6 Ref.7 Ref.8 Ref.10
Cofactor	Binds 1 Fe2+ ion per subunit.
Enzyme regulation	Activated by ascorbate. Ref.6
Subunit structure	Interacts with the TRIP4 complex, notably composed of ASCC3. Ref.10
Subcellular location	Cytoplasm. Nucleus Ref.6 Ref.7 Ref.9.
Tissue specificity	Ubiquitous. Detected in heart, pancreas, skeletal muscle, thymus, testis, ovary, spleen, prostate, small intestine, peripheral blood leukocytes, urinary bladder and colon. Ref.6 Ref.8 Ref.9
Sequence similarities	Belongs to the alkB family. Contains 1 Fe2OG dioxygenase domain.
Sequence caution	The sequence AAH15155.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	DNA damage DNA repair
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	Iron Metal-binding Vitamin C
Molecular function	Dioxygenase Oxidoreductase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA dealkylation involved in DNA repair Inferred from direct assay Ref.11Ref.10. Source: UniProtKB cell proliferation Inferred from mutant phenotype Ref.10. Source: UniProtKB oxidative single-stranded DNA demethylation Inferred from direct assay Ref.11. Source: UniProtKB
Cellular_component	mitochondrion Inferred from direct assay. Source: HPA nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	DNA-N1-methyladenine dioxygenase activity Inferred from direct assay Ref.11. Source: UniProtKB L-ascorbic acid binding Inferred from electronic annotation. Source: UniProtKB-KW cytosine C-5 DNA demethylase activity Inferred from electronic annotation. Source: Compara ferrous iron binding Inferred from direct assay Ref.11. Source: UniProtKB oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q96Q83-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q96Q83-2)

The sequence of this isoform differs from the canonical sequence as follows:
     73-74: DR → E
     125-172: ITYQQPRLTA...NRIEENTGHT → SILQLTFKKS...ILTRTRLWAP
     173-286: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 286

286

Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3

PRO_0000239278

Regions

Domain

172 – 278

107

Fe2OG dioxygenase

Region

141 – 143

3

Substrate binding By similarity

Region

179 – 181

3

Alpha-ketoglutarate binding

Region

269 – 275

7

Alpha-ketoglutarate binding

Sites

Metal binding

191

1

Iron; catalytic

Metal binding

193

1

Iron; catalytic

Metal binding

257

1

Iron; catalytic

Binding site

115

1

Substrate By similarity

Binding site

194

1

Substrate By similarity

Site

177

1

Susceptible to oxidation

Natural variations

Alternative sequence

73 – 74

2

DR → E in isoform 2.

VSP_019125

Alternative sequence

125 – 172

48

ITYQQ…NTGHT → SILQLTFKKSAPVSGTATAP QSCWYERPSPPHIPGPAILT RTRLWAP in isoform 2.

VSP_019126

Alternative sequence

173 – 286

114

Missing in isoform 2.

VSP_019127

Natural variant

164

1

R → C. Ref.2
Corresponds to variant rs2271815 [ dbSNP | Ensembl ].

VAR_026632

Natural variant

228

1

D → E. Ref.2 Ref.5
Corresponds to variant rs2434470 [ dbSNP | Ensembl ].

VAR_026631

Experimental info

Mutagenesis

122

1

R → A: Decreases activity towards ssDNA by 25%. Loss of activity towards dsDNA.

Mutagenesis

123

1

E → A: Strongly increases activity towards dsDNA, possibly by facilitating access to the active site.

Mutagenesis

131

1

R → A: Loss of activity.

Mutagenesis

177

1

L → A or N: Loss of activity against 1-methyladenine.

Mutagenesis

177

1

L → E or Q: Loss of activity.

Mutagenesis

177

1

L → I: Decreases activity against 1-methyladenine.

Mutagenesis

177

1

L → M: No effect.

Mutagenesis

179

1

N → A: Decreases activity by about 60%.

Mutagenesis

181

1

Y → A: Strong decrease of activity.

Mutagenesis

189

1

D → A: Strongly increases activity towards dsDNA, possibly by facilitating access to the active site.

Mutagenesis

191

1

H → A: Loss of activity.

Mutagenesis

193

1

D → A: Loss of activity. Ref.8

Mutagenesis

257

1

H → A: Decreases activity by about 65%. Ref.8 Ref.10

Mutagenesis

269

1

R → A: Strong decrease of activity.

Mutagenesis

271

1

N → A: No effect.

Mutagenesis

275

1

R → A: Loss of activity.

Secondary structure

1

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286

Helix Strand Turn

Details...

Beta strand

74 – 81

8

Beta strand

84 – 86

3

Beta strand

88 – 93

6

Helix

99 – 112

14

Beta strand

119 – 124

6

Beta strand

126 – 128

3

Beta strand

130 – 137

8

Helix

145 – 148

4

Beta strand

151 – 153

3

Helix

156 – 169

14

Beta strand

175 – 181

7

Beta strand

188 – 191

4

Helix

196 – 198

3

Beta strand

204 – 211

8

Beta strand

213 – 219

7

Beta strand

234 – 239

6

Beta strand

244 – 249

6

Helix

251 – 254

4

Beta strand

255 – 259

5

Beta strand

269 – 275

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: F6563635B1F217D7	FASTA	286	33,375
	10 20 30 40 50 60 MEEKRRRARV QGAWAAPVKS QAIAQPATTA KSHLHQKPGQ TWKNKEHHLS DREFVFKEPQ 70 80 90 100 110 120 QVVRRAPEPR VIDREGVYEI SLSPTGVSRV CLYPGFVDVK EADWILEQLC QDVPWKQRTG 130 140 150 160 170 180 IREDITYQQP RLTAWYGELP YTYSRITMEP NPHWHPVLRT LKNRIEENTG HTFNSLLCNL 190 200 210 220 230 240 YRNEKDSVDW HSDDEPSLGR CPIIASLSFG ATRTFEMRKK PPPEENGDYT YVERVKIPLD 250 260 270 280 HGTLLIMEGA TQADWQHRVP KEYHSREPRV NLTFRTVYPD PRGAPW
	Isoform 2 [UniParc]. Checksum: 9BC42BA5B40B035C	FASTA	170	19,310
	10 20 30 40 50 60 MEEKRRRARV QGAWAAPVKS QAIAQPATTA KSHLHQKPGQ TWKNKEHHLS DREFVFKEPQ 70 80 90 100 110 120 QVVRRAPEPR VIEEGVYEIS LSPTGVSRVC LYPGFVDVKE ADWILEQLCQ DVPWKQRTGI 130 140 150 160 170 REDSILQLTF KKSAPVSGTA TAPQSCWYER PSPPHIPGPA ILTRTRLWAP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Homo sapiens mRNA expressed in prostate cancer and thymus." Tsujikawa K., Konishi N., Ono Y., Ichijou T., Sakamoto K., Yamamoto H. Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Fetal thymus and Prostatic carcinoma.
[2]	NIEHS SNPs program Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CYS-164 AND GLU-228.
[3]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] (ISOFORMS 1 AND 2), VARIANT GLU-228. Tissue: Lung and PNS.
[6]	"Reversal of DNA alkylation damage by two human dioxygenases." Duncan T., Trewick S.C., Koivisto P., Bates P.A., Lindahl T., Sedgwick B. Proc. Natl. Acad. Sci. U.S.A. 99:16660-16665(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[7]	"Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA." Aas P.A., Otterlei M., Falnes P.O., Vaagboe C.B., Skorpen F., Akbari M., Sundheim O., Bjoeraas M., Slupphaug G., Seeberg E., Krokan H.E. Nature 421:859-863(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[8]	"Repair of methylation damage in DNA and RNA by mammalian AlkB homologues." Lee D.-H., Jin S.-G., Cai S., Chen Y., Pfeifer G.P., O'Connor T.R. J. Biol. Chem. 280:39448-39459(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ASP-193 AND HIS-257, TISSUE SPECIFICITY.
[9]	"Expression and sub-cellular localization of human ABH family molecules." Tsujikawa K., Koike K., Kitae K., Shinkawa A., Arima H., Suzuki T., Tsuchiya M., Makino Y., Furukawa T., Konishi N., Yamamoto H. J. Cell. Mol. Med. 11:1105-1116(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[10]	"DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation." Dango S., Mosammaparast N., Sowa M.E., Xiong L.J., Wu F., Park K., Rubin M., Gygi S., Harper J.W., Shi Y. Mol. Cell 44:373-384(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH ALKBH3, MUTAGENESIS OF HIS-257.
[11]	"Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage." Sundheim O., Vaagboe C.B., Bjoeraas M., Sousa M.M.L., Talstad V., Aas P.A., Drabloes F., Krokan H.E., Tainer J.A., Slupphaug G. EMBO J. 25:3389-3397(2006) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 70-286 IN COMPLEX WITH ALPHA-KETOGLUTARATE AND IRON, MASS SPECTROMETRY, OXIDATION AT LEU-177.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB042029 mRNA. Translation: BAB70508.1.
DQ196343 Genomic DNA. Translation: ABA27096.1.
AC087521 Genomic DNA. No translation available.
CH471064 Genomic DNA. Translation: EAW68078.1.
BC015155 mRNA. Translation: AAH15155.1. Different initiation.
BC103812 mRNA. Translation: AAI03813.1.
BC103813 mRNA. Translation: AAI03814.1.
BC103814 mRNA. Translation: AAI03815.1.
BC067257 mRNA. Translation: AAH67257.1.

IPI

IPI00076597.
IPI00433171.

RefSeq

NP_631917.1. NM_139178.3.

UniGene

Hs.720708.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2IUW	X-ray	1.50	A	70-286	[»]

ProteinModelPortal

Q96Q83.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000302232.

PTM databases

PhosphoSite

Q96Q83.

Polymorphism databases

DMDM

74752087.

Proteomic databases

PaxDb

Q96Q83.

PRIDE

Q96Q83.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000302708; ENSP00000302232; ENSG00000166199.
ENST00000378840; ENSP00000368117; ENSG00000166199.
ENST00000530803; ENSP00000436788; ENSG00000166199.

GeneID

221120.

KEGG

hsa:221120.

UCSC

uc001mxs.2. human.

Organism-specific databases

CTD

221120.

GeneCards

GC11P043859.

HGNC

HGNC:30141. ALKBH3.

HPA

CAB005007.
HPA009674.

MIM

610603. gene.

neXtProt

NX_Q96Q83.

PharmGKB

PA143485293.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG3145.

HOGENOM

HOG000207105.

HOVERGEN

HBG056732.

InParanoid

Q96Q83.

KO

K10860.

OMA

DRGPRIN.

OrthoDB

EOG41JZCZ.

PhylomeDB

Q96Q83.

Enzyme and pathway databases

Reactome

REACT_216. DNA Repair.

Gene expression databases

ArrayExpress

Q96Q83.

Bgee

Q96Q83.

CleanEx

HS_ALKBH3.

Genevestigator

Q96Q83.

GermOnline

ENSG00000166199. Homo sapiens.

Family and domain databases

InterPro

IPR005123. Oxoglu/Fe-dep_dioxygenase.
[Graphical view]

Pfam

PF13532. 2OG-FeII_Oxy_2. 1 hit.
[Graphical view]

PROSITE

PS51471. FE2OG_OXY. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00126. Vitamin C.

EvolutionaryTrace

Q96Q83.

GenomeRNAi

221120.

NextBio

91204.

SOURCE

Search...

Entry information

Entry name

ALKB3_HUMAN

Accession

Primary (citable) accession number: Q96Q83
Secondary accession number(s): A6NDJ1 , Q3SYI0, Q6NX57, Q96BU8

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2006
Last sequence update:	December 1, 2001
Last modified:	May 1, 2013
This is version 100 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.