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Protein

Nucleic acid dioxygenase ALKBH1

Gene

Alkbh1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Dioxygenase that acts as on nucleic acids, such as DNA and tRNA (PubMed:27027282, PubMed:27745969). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:27027282). A number of activities have been described for this dioxygenase, but recent results suggest that it mainly acts as on tRNAs and mediates their demethylation or oxidation depending on the context and subcellular compartment (By similarity). Mainly acts as a tRNA demethylase by removing N1-methyladenine from various tRNAs, with a preference for N1-methyladenine at position 58 (m1A58) present on a stem loop structure of tRNAs (PubMed:27745969). Acts as a regulator of translation initiation and elongation in response to glucose deprivation: regulates both translation initiation, by mediating demethylation of tRNA(Met), and translation elongation, N1-methyladenine-containing tRNAs being preferentially recruited to polysomes to promote translation elongation (By similarity). In mitochondrion, specifically interacts with mt-tRNA(Met) and mediates oxidation of mt-tRNA(Met) methylated at cytosine(34) to form 5-formylcytosine (f5c) at this position (By similarity). mt-tRNA(Met) containing the f5c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation (By similarity). Specifically demethylates DNA methylated on the 6th position of adenine (N6-methyladenosine) DNA (PubMed:27027282). N6-methyladenosine (m6A) DNA is present at some L1 elements in embryonic stem cells and probably promotes their silencing (PubMed:27027282). Also able to repair alkylated single-stranded DNA and RNA containing 3-methylcytosine by oxidative demethylation, but with low activity (By similarity). Also has DNA lyase activity and introduces double-stranded breaks at abasic sites: cleaves both single-stranded DNA and double-stranded DNA at abasic sites, with the greatest activity towards double-stranded DNA with two abasic sites (By similarity). DNA lyase activity does not require alpha-ketboglutarate and iron and leads to the formation of an irreversible covalent protein-DNA adduct with the 5' DNA product (By similarity). DNA lyase activity is not required during base excision repair and class switch recombination of the immunoglobulin heavy chain during B lymphocyte activation (PubMed:23825659). May play a role in placental trophoblast lineage differentiation (PubMed:18163532).By similarity4 Publications

Catalytic activityi

N6-methyladenine in DNA + 2-oxoglutarate + O2 = adenine in DNA + formaldehyde + succinate + CO2.1 Publication
The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate.By similarity
DNA-base-CH3 + 2-oxoglutarate + O2 = DNA-base + formaldehyde + succinate + CO2.By similarity
N1-methyladenine in tRNA + 2-oxoglutarate + O2 = adenine in tRNA + formaldehyde + succinate + CO2.By similarity
5-methylcytosine(34) in mitochondrial tRNA(Met)+ 2-oxoglutarate + O2 = 5-formylcytosine(34) in mitochondrial tRNA(Met) + formaldehyde + succinate + CO2.By similarity

Cofactori

Fe2+PROSITE-ProRule annotation1 PublicationNote: Binds 1 Fe2+ ion per subunit.PROSITE-ProRule annotation

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei144SubstrateBy similarity1
Metal bindingi231Iron; catalyticPROSITE-ProRule annotation1
Metal bindingi233Iron; catalyticPROSITE-ProRule annotation1 Publication1
Binding sitei233SubstrateBy similarity1
Metal bindingi287Iron; catalyticPROSITE-ProRule annotation1

GO - Molecular functioni

GO - Biological processi

  • cell differentiation Source: MGI
  • developmental growth Source: MGI
  • DNA dealkylation involved in DNA repair Source: UniProtKB
  • DNA demethylation Source: UniProtKB
  • DNA repair Source: UniProtKB
  • in utero embryonic development Source: MGI
  • negative regulation of neuron apoptotic process Source: MGI
  • neuron migration Source: MGI
  • neuron projection development Source: MGI
  • oxidative demethylation Source: UniProtKB
  • oxidative single-stranded DNA demethylation Source: GO_Central
  • placenta development Source: MGI
  • regulation of gene expression Source: MGI
  • regulation of mitochondrial translation Source: UniProtKB
  • regulation of translational elongation Source: MGI
  • regulation of translational initiation Source: UniProtKB
  • RNA repair Source: UniProtKB
  • tRNA demethylation Source: UniProtKB
  • tRNA wobble cytosine modification Source: UniProtKB

Keywordsi

Molecular functionDioxygenase, Lyase, Oxidoreductase
Biological processDNA damage, DNA repair, RNA repair, Translation regulation
LigandIron, Metal-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Nucleic acid dioxygenase ALKBH1Curated (EC:1.14.11.-1 Publication)
Alternative name(s):
Alkylated DNA repair protein alkB homolog 1
Alpha-ketoglutarate-dependent dioxygenase ABH1By similarity
DNA 6mA demethylase1 Publication
DNA N6-methyl adenine demethylase1 Publication (EC:1.14.11.-1 Publication)
DNA lyase ABH1By similarity (EC:4.2.99.18By similarity)
DNA oxidative demethylase ALKBH1 (EC:1.14.11.33By similarity)
tRNA N1-methyl adenine demethylaseBy similarity (EC:1.14.11.-By similarity)
Gene namesi
Name:Alkbh1Imported
Synonyms:AbhBy similarity, Alkbh
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 12

Organism-specific databases

MGIiMGI:2384034. Alkbh1.

Subcellular locationi

GO - Cellular componenti

  • mitochondrion Source: UniProtKB
  • nuclear euchromatin Source: MGI

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Deficiency results in 80% reduction of the litter size due to embryonic lethality (PubMed:21072209, PubMed:23825659). Surviving pups exhibit a gender bias in favor of males (70% males and 30% females) (PubMed:21072209, PubMed:23825659). Intrauterine growth retardation and placental defects. Altered expression of trophoblast lineage-specific genes (PubMed:18163532). Increased N6-methyladenosine (m6A) DNA (PubMed:27027282). No effect on H2AK118 or H2AK119 methylation, suggesting that Alkbh1 does not act as a histone demethylase in vivo (PubMed:27027282). Cells show an strong increase of N1-methyladenine-containing tRNAs (PubMed:27745969).4 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi233D → A: Loss of activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003864531 – 389Nucleic acid dioxygenase ALKBH1Add BLAST389

Proteomic databases

EPDiP0CB42.
MaxQBiP0CB42.
PaxDbiP0CB42.
PRIDEiP0CB42.

PTM databases

iPTMnetiP0CB42.
PhosphoSitePlusiP0CB42.

Expressioni

Tissue specificityi

In adult organs, highly expressed in testis, eye, brain and kidney.1 Publication

Developmental stagei

Weak expression throughout the embryo at E8.5. As the cells migrate and differentiate during organogenesis, expressed in the spinal cord, forebrain and branchial arches at E9.5, and also in limb buds at E10.5. Peak expression at E11.5 in the frontonasal process including telencephalon, maxillary, mandibular and hyoid arches, upper and lower limb buds and midbrain and rhombomere 1 roof plates. Expression decreases considerably from E11.5 to E12.5 (PubMed:21072209). At E8.5 is highly expressed in the chorion and the ectoplacental cone. At E10.5 is highly expressed in multiple trophoblast lineages (spongiotrophoblasts, giant cell trophoblasts, glycogen cells, and labyrinthine trophoblasts). The highest placental level is at E9.5 and subsequently decreases until parturition (PubMed:18163532).2 Publications

Gene expression databases

BgeeiENSMUSG00000079036.
ExpressionAtlasiP0CB42. baseline and differential.
GenevisibleiP0CB42. MM.

Interactioni

Subunit structurei

Monomer (By similarity). Interacts with DNAJB6 (PubMed:18163532).By similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
Dnajb6O54946-22EBI-13941048,EBI-13941040

Protein-protein interaction databases

IntActiP0CB42. 1 interactor.
STRINGi10090.ENSMUSP00000124565.

Structurei

3D structure databases

ProteinModelPortaliP0CB42.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini213 – 347Fe2OG dioxygenasePROSITE-ProRule annotationAdd BLAST135

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 127Interaction with DNAJB61 PublicationAdd BLAST127
Regioni86 – 389tRNA-bindingBy similarityAdd BLAST304
Regioni175 – 177Substrate bindingBy similarity3
Regioni220 – 222Alpha-ketoglutarate bindingBy similarity3
Regioni338 – 344Alpha-ketoglutarate bindingBy similarity7

Phylogenomic databases

eggNOGiKOG2731. Eukaryota.
COG3145. LUCA.
GeneTreeiENSGT00390000004599.
HOGENOMiHOG000033905.
InParanoidiP0CB42.
KOiK10765.
OMAiCYHAVPR.
OrthoDBiEOG091G0A10.
PhylomeDBiP0CB42.
TreeFamiTF314609.

Family and domain databases

Gene3Di2.60.120.590. 1 hit.
InterProiView protein in InterPro
IPR004574. Alkb.
IPR027450. AlkB-like.
IPR005123. Oxoglu/Fe-dep_dioxygenase.
PANTHERiPTHR16557. PTHR16557. 1 hit.
PfamiView protein in Pfam
PF13532. 2OG-FeII_Oxy_2. 1 hit.
TIGRFAMsiTIGR00568. alkb. 1 hit.
PROSITEiView protein in PROSITE
PS51471. FE2OG_OXY. 1 hit.

Sequencei

Sequence statusi: Complete.

P0CB42-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGKMAAAVAS LATLAAEPRE DAFRKLFRFY RQSRPGTADL GAVIDFSEAH
60 70 80 90 100
LARSPKPGVP QVVRFPLNVS SVTERDAERV GLEPVSKWRA YGLEGYPGFI
110 120 130 140 150
FIPNPFLPGC QRHWVKQCLK LYSQKPNVCN LDKHMTKEET QGLWEQSKEV
160 170 180 190 200
LRSKEVTKRR PRSLLERLRW VTLGYHYNWD SKKYSADHYT PFPSDLAFLS
210 220 230 240 250
EQVATACGFQ GFQAEAGILN YYRLDSTLGI HVDRSELDHS KPLLSFSFGQ
260 270 280 290 300
SAIFLLGGLK RDEAPTAMFM HSGDIMVMSG FSRLLNHAVP RVLPHPDGEC
310 320 330 340 350
LPHCLETPLP AVLPSNSLVE PCSVEDWQVC ATYLRTARVN MTVRQVLATG
360 370 380
QDFPLEPVEE TKRDIAADGL CHLHDPNSPV KRKRLNPNS
Length:389
Mass (Da):43,746
Last modified:October 13, 2009 - v1
Checksum:iD18C019F0CB9C0A5
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
CT030249 Genomic DNA. No translation available.
CCDSiCCDS49120.1.
RefSeqiNP_001096035.1. NM_001102565.1.
UniGeneiMm.486235.

Genome annotation databases

EnsembliENSMUST00000162961; ENSMUSP00000124565; ENSMUSG00000079036.
GeneIDi211064.
KEGGimmu:211064.
UCSCiuc007oix.1. mouse.

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiALKB1_MOUSE
AccessioniPrimary (citable) accession number: P0CB42
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 13, 2009
Last sequence update: October 13, 2009
Last modified: June 7, 2017
This is version 67 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

H2A histone demethylase activity was observed in vitro (PubMed:22961808). The relevance of such activity is however unclear and additional experimental evidence would be needed to confirm this activity in vivo.1 Publication
The DNA N6-methyl adenine demethylase activity is subject to discussion. While DNA N6-methyl adenine demethylase activity was observed by a report (PubMed:27027282). Another group was unable to detect clear DNA N6-methyl adenine demethylase activity in vivo (PubMed:27745969).2 Publications

Keywords - Technical termi

Complete proteome, Multifunctional enzyme, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot