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Protein

E3 ubiquitin-protein ligase RFWD3

Gene

RFWD3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658). Plays a key role in RPA-mediated DNA damage signaling and repair (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658). Acts by mediating ubiquitination of the RPA complex (RPA1, RPA2 and RPA3 subunits) and RAD51 at stalled replication forks, leading to remove them from DNA damage sites and promote homologous recombination (PubMed:26474068, PubMed:28575657, PubMed:28575658). Also mediates the ubiquitination of p53/TP53 in the late response to DNA damage, and acts as a positive regulator of p53/TP53 stability, thereby regulating the G1/S DNA damage checkpoint (PubMed:20173098). May act by catalyzing the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:20173098). In response to ionizing radiation, interacts with MDM2 and enhances p53/TP53 ubiquitination, possibly by restricting MDM2 from extending polyubiquitin chains on ubiquitinated p53/TP53 (PubMed:20173098).6 Publications

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.3 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.3 Publications
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri287 – 331RING-type; degeneratePROSITE-ProRule annotationAdd BLAST45

GO - Molecular functioni

  • MDM2/MDM4 family protein binding Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • p53 binding Source: UniProtKB
  • ubiquitin-protein transferase activity Source: UniProtKB

GO - Biological processi

  • cellular response to DNA damage stimulus Source: UniProtKB
  • double-strand break repair via homologous recombination Source: UniProtKB
  • interstrand cross-link repair Source: UniProtKB
  • mitotic G1 DNA damage checkpoint Source: UniProtKB
  • protein ubiquitination Source: UniProtKB
  • regulation of DNA damage checkpoint Source: UniProtKB
  • replication fork processing Source: UniProtKB
  • response to ionizing radiation Source: UniProtKB

Keywordsi

Molecular functionTransferase
Biological processDNA damage, DNA repair, Ubl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

SignaLinkiQ6PCD5
UniPathwayiUPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase RFWD3Curated (EC:2.3.2.273 Publications)
Alternative name(s):
RING finger and WD repeat domain-containing protein 3
RING finger protein 201
Gene namesi
Name:RFWD3Imported
Synonyms:RNF201Imported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

EuPathDBiHostDB:ENSG00000168411.13
HGNCiHGNC:25539 RFWD3
MIMi614151 gene
neXtProtiNX_Q6PCD5

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Fanconi anemia, complementation group W (FANCW): A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair (PubMed:28575657). The disease is caused by mutations affecting the gene represented in this entry.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi36 – 38LQP → AAA: Decreased interaction with RAD51; when associated with 53-A--A-55 and 70-A--A-72. 1 Publication3
Mutagenesisi46S → A: Markedly decreases phosphorylation following ionizing radiation and abolishes ability to stimulate p53/TP53 ubiquitination; when associated with A-63. 1 Publication1
Mutagenesisi53 – 55LQP → AAA: Decreased interaction with RAD51; when associated with 36-A--A-38 and 70-A--A-72. 1 Publication3
Mutagenesisi63S → A: Markedly decreases phosphorylation following ionizing radiation and abolishes ability to stimulate p53/TP53 ubiquitination; when associated with A-46. 1 Publication1
Mutagenesisi70 – 72LQP → AAA: Decreased interaction with RAD51; when associated with 36-A--A-38 and 53-A--A-55. 1 Publication3
Mutagenesisi315C → A: Abolishes ability to stimulate p53/TP53 ubiquitination. No effect on nuclear localization in response to DNA damage. 4 Publications1
Mutagenesisi499Q → A: Does not affect interaction with the RPA complex and subsequent recruitment at DNA damage sites. 1 Publication1
Mutagenesisi518L → A: Does not affect interaction with the RPA complex and subsequent recruitment at DNA damage sites. 1 Publication1
Mutagenesisi543W → A: Abolishes interaction with the RPA complex and subsequent recruitment at DNA damage sites. 1 Publication1

Keywords - Diseasei

Disease mutation, Fanconi anemia

Organism-specific databases

DisGeNETi55159
OpenTargetsiENSG00000168411
PharmGKBiPA134960063

Polymorphism and mutation databases

BioMutaiRFWD3
DMDMi126253679

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002782341 – 774E3 ubiquitin-protein ligase RFWD3Add BLAST774

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei46Phosphoserine; by ATM and ATR3 Publications1
Modified residuei63Phosphoserine; by ATM and ATR3 Publications1

Post-translational modificationi

Phosphorylated at Ser-46 and Ser-63 upon DNA damage by ATM or ATR. ATM phosphorylation occurs at early times upon DNA damage, while ATR is the major kinase at later times. Phosphorylation by ATM and ATR is required to stabilize p53/TP53. Part of the phosphorylation depends upon RPA2 presence.4 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ6PCD5
MaxQBiQ6PCD5
PaxDbiQ6PCD5
PeptideAtlasiQ6PCD5
PRIDEiQ6PCD5

PTM databases

iPTMnetiQ6PCD5
PhosphoSitePlusiQ6PCD5

Expressioni

Developmental stagei

Up-regulated in the S-G2 phase.1 Publication

Gene expression databases

BgeeiENSG00000168411
CleanExiHS_RFWD3
ExpressionAtlasiQ6PCD5 baseline and differential
GenevisibleiQ6PCD5 HS

Organism-specific databases

HPAiHPA048258
HPA075649

Interactioni

Subunit structurei

Interacts with MDM2 and p53/TP53 (PubMed:20173098). Binds to the RPA complex via direct interaction with RPA2 (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575658). Interacts with RAD51 (PubMed:28575658).5 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • MDM2/MDM4 family protein binding Source: UniProtKB
  • p53 binding Source: UniProtKB

Protein-protein interaction databases

BioGridi120460, 53 interactors
DIPiDIP-52688N
IntActiQ6PCD5, 41 interactors
MINTiQ6PCD5
STRINGi9606.ENSP00000354361

Structurei

3D structure databases

ProteinModelPortaliQ6PCD5
SMRiQ6PCD5
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati495 – 537WD 1Add BLAST43
Repeati539 – 577WD 2Add BLAST39
Repeati583 – 628WD 3Add BLAST46

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili361 – 413Sequence analysisAdd BLAST53

Domaini

The coiled coil domain may be involved in RPA2-binding.1 Publication

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri287 – 331RING-type; degeneratePROSITE-ProRule annotationAdd BLAST45

Keywords - Domaini

Coiled coil, Repeat, WD repeat, Zinc-finger

Phylogenomic databases

eggNOGiKOG1645 Eukaryota
ENOG410XPPE LUCA
GeneTreeiENSGT00390000008931
HOVERGENiHBG093895
InParanoidiQ6PCD5
KOiK15691
OMAiLEGACFW
OrthoDBiEOG091G05D0
PhylomeDBiQ6PCD5
TreeFamiTF323359

Family and domain databases

Gene3Di2.130.10.10, 1 hit
3.30.40.10, 1 hit
InterProiView protein in InterPro
IPR037381 RFWD3
IPR015943 WD40/YVTN_repeat-like_dom_sf
IPR001680 WD40_repeat
IPR036322 WD40_repeat_dom_sf
IPR001841 Znf_RING
IPR013083 Znf_RING/FYVE/PHD
PANTHERiPTHR16047 PTHR16047, 1 hit
PfamiView protein in Pfam
PF13639 zf-RING_2, 1 hit
SMARTiView protein in SMART
SM00184 RING, 1 hit
SM00320 WD40, 3 hits
SUPFAMiSSF50978 SSF50978, 2 hits
PROSITEiView protein in PROSITE
PS50089 ZF_RING_2, 1 hit

Sequencei

Sequence statusi: Complete.

Q6PCD5-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAHEAMEYDV QVQLNHAEQQ PAPAGMASSQ GGPALLQPVP ADVVSSQGVP
60 70 80 90 100
SILQPAPAEV ISSQATPPLL QPAPQLSVDL TEVEVLGEDT VENINPRTSE
110 120 130 140 150
QHRQGSDGNH TIPASSLHSM TNFISGLQRL HGMLEFLRPS SSNHSVGPMR
160 170 180 190 200
TRRRVSASRR ARAGGSQRTD SARLRAPLDA YFQVSRTQPD LPATTYDSET
210 220 230 240 250
RNPVSEELQV SSSSDSDSDS SAEYGGVVDQ AEESGAVILE EQLAGVSAEQ
260 270 280 290 300
EVTCIDGGKT LPKQPSPQKS EPLLPSASMD EEEGDTCTIC LEQWTNAGDH
310 320 330 340 350
RLSALRCGHL FGYRCISTWL KGQVRKCPQC NKKARHSDIV VLYARTLRAL
360 370 380 390 400
DTSEQERMKS SLLKEQMLRK QAELESAQCR LQLQVLTDKC TRLQRRVQDL
410 420 430 440 450
QKLTSHQSQN LQQPRGSQAW VLSCSPSSQG QHKHKYHFQK TFTVSQAGNC
460 470 480 490 500
RIMAYCDALS CLVISQPSPQ ASFLPGFGVK MLSTANMKSS QYIPMHGKQI
510 520 530 540 550
RGLAFSSYLR GLLLSASLDN TIKLTSLETN TVVQTYNAGR PVWSCCWCLD
560 570 580 590 600
EANYIYAGLA NGSILVYDVR NTSSHVQELV AQKARCPLVS LSYMPRAASA
610 620 630 640 650
AFPYGGVLAG TLEDASFWEQ KMDFSHWPHV LPLEPGGCID FQTENSSRHC
660 670 680 690 700
LVTYRPDKNH TTIRSVLMEM SYRLDDTGNP ICSCQPVHTF FGGPTCKLLT
710 720 730 740 750
KNAIFQSPEN DGNILVCTGD EAANSALLWD AASGSLLQDL QTDQPVLDIC
760 770
PFEVNRNSYL ATLTEKMVHI YKWE
Length:774
Mass (Da):85,094
Last modified:February 20, 2007 - v3
Checksum:iEF6E0E186FD2E580
GO

Sequence cautioni

The sequence BAA91662 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAF83889 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAG38132 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti221S → P in BAF83889 (PubMed:14702039).Curated1
Sequence conflicti552A → T in BAA91662 (PubMed:14702039).Curated1
Sequence conflicti597A → V in BAA91662 (PubMed:14702039).Curated1
Sequence conflicti741Q → R in BAB14169 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03070090T → N. Corresponds to variant dbSNP:rs8058922Ensembl.1
Natural variantiVAR_030701392R → K1 PublicationCorresponds to variant dbSNP:rs17854997Ensembl.1
Natural variantiVAR_030702564I → V1 PublicationCorresponds to variant dbSNP:rs7193541Ensembl.1
Natural variantiVAR_078953639I → K in FANCW; abolishes interaction with the RPA complex and subsequent recruitment at DNA damage sites. 1 Publication1
Natural variantiVAR_030703770I → T1 PublicationCorresponds to variant dbSNP:rs17854996Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK001382 mRNA Translation: BAA91662.1 Different initiation.
AK022673 mRNA Translation: BAB14169.1
AK291200 mRNA Translation: BAF83889.1 Different initiation.
AK315786 mRNA Translation: BAG38132.1 Different initiation.
AC109599 Genomic DNA No translation available.
CH471114 Genomic DNA Translation: EAW95680.1
CH471114 Genomic DNA Translation: EAW95681.1
BC002574 mRNA Translation: AAH02574.2
BC059371 mRNA Translation: AAH59371.2
CCDSiCCDS32486.1
RefSeqiNP_060594.3, NM_018124.3
XP_005256078.1, XM_005256021.4
XP_005256079.1, XM_005256022.4
XP_011521493.1, XM_011523191.2
XP_016878880.1, XM_017023391.1
UniGeneiHs.567525

Genome annotation databases

EnsembliENST00000361070; ENSP00000354361; ENSG00000168411
ENST00000571750; ENSP00000460049; ENSG00000168411
GeneIDi55159
KEGGihsa:55159
UCSCiuc002fda.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiRFWD3_HUMAN
AccessioniPrimary (citable) accession number: Q6PCD5
Secondary accession number(s): A8K585
, B2RE35, D3DUJ8, Q5XKR3, Q9H9Q3, Q9NVT4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 20, 2007
Last sequence update: February 20, 2007
Last modified: April 25, 2018
This is version 137 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health