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Protein

E3 ubiquitin-protein ligase UHRF1

Gene

Uhrf1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Multidomain protein that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification. Specifically recognizes and binds hemimethylated DNA at replication forks via its YDG domain and recruits DNMT1 methyltransferase to ensure faithful propagation of the DNA methylation patterns through DNA replication. In addition to its role in maintenance of DNA methylation, also plays a key role in chromatin modification: through its tudor-like regions and PHD-type zinc fingers, specifically recognizes and binds histone H3 trimethylated at 'Lys-9' (H3K9me3) and unmethylated at 'Arg-2' (H3R2me0), respectively, and recruits chromatin proteins. Enriched in pericentric heterochromatin where it recruits different chromatin modifiers required for this chromatin replication. Also localizes to euchromatic regions where it negatively regulates transcription possibly by impacting DNA methylation and histone modifications. Has E3 ubiquitin-protein ligase activity by mediating the ubiquitination of target proteins such as histone H3 and PML. It is still unclear how E3 ubiquitin-protein ligase activity is related to its role in chromatin in vivo. May be involved in DNA repair (By similarity).By similarity

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei313 – 3131Histone H3K4me0By similarity
Binding sitei324 – 3241Histone H3R2me0By similarity
Binding sitei327 – 3271Histone H3R2me0By similarity
Binding sitei466 – 4661MethylcytosineBy similarity
Sitei476 – 4761Required to confer preferential recognition of cytosine over thymineBy similarity
Sitei486 – 4861Required to discriminate between hemimethylated DNA versus symmetrically methylated DNABy similarity
Sitei488 – 4881Required for affinity and specificity for 5-mCpG sequenceBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri296 – 36368PHD-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri705 – 74440RING-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Ligase, Repressor

Keywords - Biological processi

Cell cycle, DNA damage, DNA repair, Transcription, Transcription regulation, Ubl conjugation pathway

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase UHRF1 (EC:6.3.2.-)
Alternative name(s):
Liver regeneration-related protein LRRG126
Ubiquitin-like PHD and RING finger domain-containing protein 1
Ubiquitin-like-containing PHD and RING finger domains protein 1
Gene namesi
Name:Uhrf1
ORF Names:Ac2-121
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi1595855. Uhrf1.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotation

  • Note: Localizes to replication foci. Enriched in pericentric heterochromatin. Also localizes to euchromatic regions (By similarity).By similarity

GO - Cellular componenti

  • cytoplasmic vesicle Source: RGD
  • euchromatin Source: UniProtKB
  • heterochromatin Source: UniProtKB
  • nuclear chromatin Source: UniProtKB
  • nuclear heterochromatin Source: GO_Central
  • plasma membrane Source: RGD
  • replication fork Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 774774E3 ubiquitin-protein ligase UHRF1PRO_0000056146Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei76 – 761PhosphoserineBy similarity
Modified residuei91 – 911PhosphoserineCombined sources
Modified residuei93 – 931PhosphoserineCombined sources
Modified residuei95 – 951PhosphoserineCombined sources
Modified residuei161 – 1611PhosphoserineBy similarity
Modified residuei284 – 2841PhosphoserineCombined sources
Modified residuei295 – 2951Phosphoserine; by PKABy similarity
Modified residuei365 – 3651PhosphoserineBy similarity
Cross-linki382 – 382Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateBy similarity
Cross-linki382 – 382Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternateBy similarity
Modified residuei396 – 3961N6-acetyllysineBy similarity
Modified residuei511 – 5111PhosphoserineBy similarity
Modified residuei542 – 5421N6-acetyllysine; alternateBy similarity
Cross-linki542 – 542Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateBy similarity
Modified residuei631 – 6311Phosphoserine; by CDK1By similarity
Modified residuei641 – 6411PhosphoserineBy similarity
Modified residuei648 – 6481PhosphoserineBy similarity
Cross-linki656 – 656Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei751 – 7511PhosphoserineCombined sources

Post-translational modificationi

Phosphorylation at Ser-295 of the linker region decreases the binding to H3K9me3. Phosphorylation at Ser-631 by CDK1 during M phase impairs interaction with USP7, preventing deubiquitination and leading to degradation by the proteasome (By similarity).By similarity
Ubiquitinated; which leads to proteasomal degradation. Autoubiquitinated; interaction with USP7 leads to deubiquitination and prevents degradation. Ubiquitination and degradation takes place during M phase, when phosphorylation at Ser-631 prevents intereaction with USP7 and subsequent deubiquitination. Polyubiquitination may be stimulated by DNA damage (By similarity).By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ7TPK1.
PRIDEiQ7TPK1.

PTM databases

iPTMnetiQ7TPK1.

Interactioni

Subunit structurei

Interacts with DNMT3A and DNMT3B. Interacts with DNMT1; the interaction is direct. Interacts with USP7; leading to its deubiquitination. Interacts with histone H3. Interacts with HDAC1, but not with HDAC2. Interacts with UHRF1BP1. Interacts with PML. Interacts with EHMT2. Binds methylated CpG containing oligonucleotides (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000066794.

Structurei

3D structure databases

ProteinModelPortaliQ7TPK1.
SMRiQ7TPK1. Positions 1-76, 289-363, 412-613, 658-774.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1 – 7878Ubiquitin-likePROSITE-ProRule annotationAdd
BLAST
Domaini416 – 578163YDGPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni129 – 20577Tudor-like 1Add
BLAST
Regioni212 – 28069Tudor-like 2Add
BLAST
Regioni293 – 2986LinkerBy similarity
Regioni330 – 3345Histone H3R2me0 bindingBy similarity
Regioni350 – 3523Histone H3R2me0 bindingBy similarity
Regioni382 – 605224Methyl-CpG binding and interaction with HDAC1By similarityAdd
BLAST
Regioni442 – 4432Required to promote base flippingBy similarity
Regioni460 – 4612Methylcytosine bindingBy similarity
Regioni463 – 4664Required for formation of a 5-methylcytosine-binding pocketBy similarity
Regioni475 – 4784Required for formation of a 5-methylcytosine-binding pocketBy similarity

Domaini

The tudor-like regions specifically recognize and bind histone H3 unmethylated at 'Arg-2' (H3R2me0), while the PHD-type zinc finger specifically recognizes and binds histone H3 trimethylated at 'Lys-9' (H3K9me3). The tudor-like regions simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first tudor-like subdomain and unmodified H3K4 (H3K4me0) within a groove between the tandem subdomains. The linker region plays a role in the formation of a histone H3-binding hole between the reader modules formed by the tudor-like regions and the PHD-type zinc finger by making extended contacts with the tandem tudor-like regions (By similarity).By similarity
The YDG domain (also named SRA domain) specifically recognizes and binds hemimethylated DNA at replication forks (DNA that is only methylated on the mother strand of replicating DNA). It contains a binding pocket that accommodates the 5-methylcytosine that is flipped out of the duplex DNA. 2 specialized loops reach through the resulting gap in the DNA from both the major and the minor grooves to read the other 3 bases of the CpG duplex. The major groove loop confers both specificity for the CpG dinucleotide and discrimination against methylation of deoxycytidine of the complementary strand. The YDG domain also recognizes and binds 5-hydroxymethylcytosine (5hmC) (By similarity).By similarity
The RING finger is required for ubiquitin ligase activity.By similarity

Sequence similaritiesi

Contains 1 PHD-type zinc finger.PROSITE-ProRule annotation
Contains 1 RING-type zinc finger.PROSITE-ProRule annotation
Contains 1 ubiquitin-like domain.PROSITE-ProRule annotation
Contains 1 YDG domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri296 – 36368PHD-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri705 – 74440RING-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiENOG410IFAP. Eukaryota.
COG3440. LUCA.
HOVERGENiHBG059298.
InParanoidiQ7TPK1.
KOiK10638.
OrthoDBiEOG76DTRX.
PhylomeDBiQ7TPK1.

Family and domain databases

Gene3Di2.30.280.10. 1 hit.
2.30.30.30. 1 hit.
3.30.40.10. 2 hits.
InterProiIPR015947. PUA-like_domain.
IPR014722. Rib_L2_dom2.
IPR003105. SRA_YDG.
IPR021991. TTD_dom.
IPR029071. Ubiquitin-rel_dom.
IPR000626. Ubiquitin_dom.
IPR011011. Znf_FYVE_PHD.
IPR001965. Znf_PHD.
IPR019787. Znf_PHD-finger.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF00628. PHD. 1 hit.
PF02182. SAD_SRA. 1 hit.
PF12148. TTD. 1 hit.
PF00240. ubiquitin. 1 hit.
[Graphical view]
SMARTiSM00249. PHD. 1 hit.
SM00184. RING. 2 hits.
SM00466. SRA. 1 hit.
SM00213. UBQ. 1 hit.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 1 hit.
SSF57903. SSF57903. 1 hit.
SSF88697. SSF88697. 1 hit.
PROSITEiPS50053. UBIQUITIN_2. 1 hit.
PS51015. YDG. 1 hit.
PS01359. ZF_PHD_1. 1 hit.
PS50016. ZF_PHD_2. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q7TPK1-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MWIQVRTMDG KETHTVNSLS RLTKVQELRK KIEELFHVEP QLQRLFYRGK
60 70 80 90 100
QMEDGHTLFD YDVRLNDTIQ LLVRQSLALP LSTKERDSEL SDSDSGYGVG
110 120 130 140 150
HSESDKSSTH GEGTADGDDK TVWEDTDLGL YKVNEYVDVR DNIFGAWFEA
160 170 180 190 200
QVVQVQKKAL SEEEPCSSSA IMAPEDDIMY HIKYDDYPEH GVDIVKAKNV
210 220 230 240 250
RARARTVIPW EDLEVGQVVM ANYNVDYPRK RGFWYDVEIC RKRQTRTARE
260 270 280 290 300
LYGNVMLLND SQLNNCRIIF VDEVLKIELP NERSPLIGSP SRRKSGPSCQ
310 320 330 340 350
YCKDDENKPC RKCACHICGG REAPEKQVLC DECDMAFHLY CLQPPLTCVP
360 370 380 390 400
PEPEWYCPSC RTDSSEVVQA GEKLKKSKKK AKMASATSSS RRDWGKGMAC
410 420 430 440 450
VGRTTECTIV PANHFGPIPG VPVGTMWRFR VQVSESGVHR PHVAGIHGRS
460 470 480 490 500
NDGAYSLVLA GGYEDDVDNG NFFTYTGSGG RDLSGNKRTA GQSSDQKLTN
510 520 530 540 550
NNRALALNCH SPINEKGAEA EDWRQGKPVR VVRNMKGGKH SKYAPAEGNR
560 570 580 590 600
YDGIYKVVKY WPEKGKSGFI VWRYLLRRDD TEPEPWTREG KDRTRQLGLT
610 620 630 640 650
MQYPEGYLEA LANKEKNRKR PAKALEQGPS SSKIGKSKRK STGPATTSPR
660 670 680 690 700
VSKKSKLEPY TLPLQQANLI KEDKGNAKLW DDVLSSLQDG PYQIFLSKVK
710 720 730 740 750
EAFQCICCQE LVFRPVTTVC QHNVCKDCLD RSFRAQVFSC PACRYDLDHS
760 770
SPTRVNQPLQ TILNQLFPGY GSGR
Length:774
Mass (Da):87,449
Last modified:June 7, 2005 - v2
Checksum:iC2FB3112F2D2EF9E
GO

Sequence cautioni

The sequence AAP86266.1 differs from that shown. Reason: Erroneous initiation. Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY321334 mRNA. Translation: AAP86266.1. Different initiation.
BC099224 mRNA. Translation: AAH99224.1.
RefSeqiNP_001008882.1. NM_001008882.1.
UniGeneiRn.54318.

Genome annotation databases

GeneIDi316129.
KEGGirno:316129.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY321334 mRNA. Translation: AAP86266.1. Different initiation.
BC099224 mRNA. Translation: AAH99224.1.
RefSeqiNP_001008882.1. NM_001008882.1.
UniGeneiRn.54318.

3D structure databases

ProteinModelPortaliQ7TPK1.
SMRiQ7TPK1. Positions 1-76, 289-363, 412-613, 658-774.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000066794.

PTM databases

iPTMnetiQ7TPK1.

Proteomic databases

PaxDbiQ7TPK1.
PRIDEiQ7TPK1.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi316129.
KEGGirno:316129.

Organism-specific databases

CTDi29128.
RGDi1595855. Uhrf1.

Phylogenomic databases

eggNOGiENOG410IFAP. Eukaryota.
COG3440. LUCA.
HOVERGENiHBG059298.
InParanoidiQ7TPK1.
KOiK10638.
OrthoDBiEOG76DTRX.
PhylomeDBiQ7TPK1.

Enzyme and pathway databases

UniPathwayiUPA00143.

Miscellaneous databases

PROiQ7TPK1.

Family and domain databases

Gene3Di2.30.280.10. 1 hit.
2.30.30.30. 1 hit.
3.30.40.10. 2 hits.
InterProiIPR015947. PUA-like_domain.
IPR014722. Rib_L2_dom2.
IPR003105. SRA_YDG.
IPR021991. TTD_dom.
IPR029071. Ubiquitin-rel_dom.
IPR000626. Ubiquitin_dom.
IPR011011. Znf_FYVE_PHD.
IPR001965. Znf_PHD.
IPR019787. Znf_PHD-finger.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF00628. PHD. 1 hit.
PF02182. SAD_SRA. 1 hit.
PF12148. TTD. 1 hit.
PF00240. ubiquitin. 1 hit.
[Graphical view]
SMARTiSM00249. PHD. 1 hit.
SM00184. RING. 2 hits.
SM00466. SRA. 1 hit.
SM00213. UBQ. 1 hit.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 1 hit.
SSF57903. SSF57903. 1 hit.
SSF88697. SSF88697. 1 hit.
PROSITEiPS50053. UBIQUITIN_2. 1 hit.
PS51015. YDG. 1 hit.
PS01359. ZF_PHD_1. 1 hit.
PS50016. ZF_PHD_2. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Liver regeneration after PH."
    Xu C.S., Li W.Q., Li Y.C., Wang G.P., Chai L.Q., Yuan J.Y., Yang K.J., Yan H.M., Chang C.F., Zhao L.F., Ma H., Wang L., Wang S.F., Han H.P., Shi J.B., Rahman S., Wang Q.N., Zhang J.B.
    Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Liver.
  2. "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] OF 381-774.
    Tissue: Thymus.
  3. "Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues."
    Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., Olsen J.V.
    Nat. Commun. 3:876-876(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-91; SER-93; SER-95; SER-284 AND SER-751, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].

Entry informationi

Entry nameiUHRF1_RAT
AccessioniPrimary (citable) accession number: Q7TPK1
Secondary accession number(s): Q4FZR4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 7, 2005
Last sequence update: June 7, 2005
Last modified: July 6, 2016
This is version 102 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  2. SIMILARITY comments
    Index of protein domains and families

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.