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Protein

E3 ubiquitin-protein ligase rififylin

Gene

RFFL

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

Functioni

E3 ubiquitin-protein ligase that regulates several biological processes through the ubiquitin-mediated proteasomal degradation of various target proteins. Mediates 'Lys-48'-linked polyubiquitination of PRR5L and its subsequent proteasomal degradation thereby indirectly regulating cell migration through the mTORC2 complex. Ubiquitinates the caspases CASP8 and CASP10, promoting their proteasomal degradation, to negatively regulate cell death downstream of death domain receptors in the extrinsic pathway of apoptosis. Negatively regulates the tumor necrosis factor-mediated signaling pathway through targeting of RIPK1 to ubiquitin-mediated proteasomal degradation. Negatively regulates p53/TP53 through its direct ubiquitination and targeting to proteasomal degradation. Indirectly, may also negatively regulate p53/TP53 through ubiquitination and degradation of SFN. May also play a role in endocytic recycling.5 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.1 Publication

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.1 Publication
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 fingeri41 – 96FYVE-typeAdd BLAST56
Zinc fingeri316 – 351RING-typePROSITE-ProRule annotationAdd BLAST36

GO - Molecular functioni

  • metal ion binding Source: UniProtKB-KW
  • p53 binding Source: UniProtKB
  • protease binding Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • ubiquitin protein ligase activity Source: UniProtKB
  • ubiquitin protein ligase binding Source: UniProtKB

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis Source: UniProtKB
  • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: UniProtKB
  • negative regulation of signal transduction by p53 class mediator Source: UniProtKB
  • negative regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  • protein K48-linked ubiquitination Source: UniProtKB
  • regulation of fibroblast migration Source: UniProtKB
  • regulation of TOR signaling Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: UniProtKB

Keywordsi

Molecular functionTransferase
Biological processApoptosis, Ubl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-6804757 Regulation of TP53 Degradation
UniPathwayiUPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase rififylinCurated (EC:2.3.2.271 Publication)
Alternative name(s):
Caspase regulator CARP2
Caspases-8 and -10-associated RING finger protein 2
Short name:
CARP-2
FYVE-RING finger protein Sakura
Short name:
Fring
RING finger and FYVE-like domain-containing protein 1
RING finger protein 189
RING finger protein 34-like
RING-type E3 ubiquitin transferase rififylinCurated
Gene namesi
Name:RFFLImported
Synonyms:RNF189, RNF34L
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000092871.16
HGNCiHGNC:24821 RFFL
MIMi609735 gene
neXtProtiNX_Q8WZ73

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

Cell membrane, Cytoplasm, Endosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi333H → A: Loss of E3 ubiquitin protein ligase activity. 1 Publication1

Organism-specific databases

DisGeNETi117584
OpenTargetsiENSG00000092871
PharmGKBiPA142671086

Polymorphism and mutation databases

BioMutaiRFFL
DMDMi74760639

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000560251 – 363E3 ubiquitin-protein ligase rififylinAdd BLAST363

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei226PhosphoserineCombined sources1
Modified residuei229PhosphoserineCombined sources1
Modified residuei232PhosphoserineBy similarity1
Modified residuei240PhosphoserineBy similarity1

Post-translational modificationi

Autoubiquitinated.By similarity
Palmitoylated.By similarity
Undergoes caspase-mediated cleavage upon death-receptor activation, by TNFSF10 for instance. May be mediated by the caspases CASP8 and CASP10 in a negative feedback loop.

Keywords - PTMi

Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ8WZ73
MaxQBiQ8WZ73
PaxDbiQ8WZ73
PeptideAtlasiQ8WZ73
PRIDEiQ8WZ73

PTM databases

iPTMnetiQ8WZ73
PhosphoSitePlusiQ8WZ73
SwissPalmiQ8WZ73

Expressioni

Tissue specificityi

Ubiquitous. Detected in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.1 Publication

Inductioni

Down-regulated upon DNA damage.1 Publication

Gene expression databases

BgeeiENSG00000092871
CleanExiHS_RFFL
ExpressionAtlasiQ8WZ73 baseline and differential
GenevisibleiQ8WZ73 HS

Organism-specific databases

HPAiCAB008096
HPA017910
HPA019492

Interactioni

Subunit structurei

Interacts with CASP8 and CASP10. Interacts with RIPK1 (via protein kinase domain); involved in RIPK1 ubiquitination. Interacts with PRR5L. Interacts (via RING-type zinc finger) with p53/TP53; involved in p53/TP53 ubiquitination. Interacts (via RING-type zinc finger) with MDM2; the interaction stabilizes MDM2.5 Publications

GO - Molecular functioni

  • p53 binding Source: UniProtKB
  • protease binding Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • ubiquitin protein ligase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi125593, 25 interactors
IntActiQ8WZ73, 2 interactors
STRINGi9606.ENSP00000326170

Structurei

Secondary structure

1363
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni48 – 50Combined sources3
Helixi57 – 59Combined sources3
Turni64 – 66Combined sources3
Helixi72 – 74Combined sources3
Helixi86 – 93Combined sources8
Turni94 – 96Combined sources3
Helixi98 – 102Combined sources5
Helixi106 – 115Combined sources10
Helixi126 – 135Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1Y02X-ray1.80A26-145[»]
ProteinModelPortaliQ8WZ73
SMRiQ8WZ73
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ8WZ73

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini101 – 120SAP 1Add BLAST20
Domaini250 – 264SAP 2Add BLAST15

Domaini

The RING-type zinc finger is required for the ubiquitination of target proteins.1 Publication
The FYVE-type zinc finger domain is required for localization to the recycling endosome membranes and the function in endocytic recycling.By similarity

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri41 – 96FYVE-typeAdd BLAST56
Zinc fingeri316 – 351RING-typePROSITE-ProRule annotationAdd BLAST36

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiKOG4275 Eukaryota
ENOG41101VR LUCA
GeneTreeiENSGT00390000012719
HOGENOMiHOG000068080
HOVERGENiHBG055079
InParanoidiQ8WZ73
KOiK20804
OMAiIMWATCC
OrthoDBiEOG091G0S1S
PhylomeDBiQ8WZ73
TreeFamiTF325195

Family and domain databases

Gene3Di3.30.40.10, 1 hit
InterProiView protein in InterPro
IPR036361 SAP_dom_sf
IPR011011 Znf_FYVE_PHD
IPR001841 Znf_RING
IPR013083 Znf_RING/FYVE/PHD
SMARTiView protein in SMART
SM00184 RING, 1 hit
SUPFAMiSSF57903 SSF57903, 1 hit
SSF68906 SSF68906, 1 hit
PROSITEiView protein in PROSITE
PS50089 ZF_RING_2, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8WZ73-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MWATCCNWFC LDGQPEEVPP PQGARMQAYS NPGYSSFPSP TGLEPSCKSC
60 70 80 90 100
GAHFANTARK QTCLDCKKNF CMTCSSQVGN GPRLCLLCQR FRATAFQREE
110 120 130 140 150
LMKMKVKDLR DYLSLHDIST EMCREKEELV LLVLGQQPVI SQEDRTRAST
160 170 180 190 200
LSPDFPEQQA FLTQPHSSMV PPTSPNLPSS SAQATSVPPA QVQENQQANG
210 220 230 240 250
HVSQDQEEPV YLESVARVPA EDETQSIDSE DSFVPGRRAS LSDLTDLEDI
260 270 280 290 300
EGLTVRQLKE ILARNFVNYK GCCEKWELME RVTRLYKDQK GLQHLVSGAE
310 320 330 340 350
DQNGGAVPSG LEENLCKICM DSPIDCVLLE CGHMVTCTKC GKRMNECPIC
360
RQYVIRAVHV FRS
Length:363
Mass (Da):40,514
Last modified:March 1, 2002 - v1
Checksum:i9456ED5A0503AFFB
GO
Isoform 2 (identifier: Q8WZ73-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     296-303: Missing.

Show »
Length:355
Mass (Da):39,713
Checksum:i0F22B82AD059DE03
GO
Isoform 3 (identifier: Q8WZ73-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     197-224: Missing.
     296-303: Missing.

Show »
Length:327
Mass (Da):36,633
Checksum:i34CE0CD40417BE8E
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti127E → G in AAH28424 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_015751197 – 224Missing in isoform 3. 1 PublicationAdd BLAST28
Alternative sequenceiVSP_015752296 – 303Missing in isoform 2 and isoform 3. 2 Publications8

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF434816 mRNA Translation: AAL30771.1
AY098935 mRNA Translation: AAM29181.1
AK093112 mRNA Translation: BAC04059.1
CR933651 mRNA Translation: CAI45952.1
CH471147 Genomic DNA Translation: EAW80172.1
CH471147 Genomic DNA Translation: EAW80173.1
CH471147 Genomic DNA Translation: EAW80176.1
CH471147 Genomic DNA Translation: EAW80177.1
CH471147 Genomic DNA Translation: EAW80178.1
BC015681 mRNA Translation: AAH15681.2
BC028424 mRNA Translation: AAH28424.1
CCDSiCCDS11286.1 [Q8WZ73-1]
RefSeqiNP_001017368.1, NM_001017368.1 [Q8WZ73-1]
UniGeneiHs.13680

Genome annotation databases

EnsembliENST00000315249; ENSP00000326170; ENSG00000092871 [Q8WZ73-1]
ENST00000394597; ENSP00000378096; ENSG00000092871 [Q8WZ73-1]
ENST00000413582; ENSP00000408513; ENSG00000092871 [Q8WZ73-2]
ENST00000415395; ENSP00000412322; ENSG00000092871 [Q8WZ73-1]
ENST00000447669; ENSP00000389832; ENSG00000092871 [Q8WZ73-1]
ENST00000584655; ENSP00000463035; ENSG00000092871 [Q8WZ73-3]
GeneIDi117584
KEGGihsa:117584
UCSCiuc002hin.2 human [Q8WZ73-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiRFFL_HUMAN
AccessioniPrimary (citable) accession number: Q8WZ73
Secondary accession number(s): E1P633
, Q8NHW0, Q8TBY7, Q96BE6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 27, 2005
Last sequence update: March 1, 2002
Last modified: April 25, 2018
This is version 152 of the entry and version 1 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

3D-structure, Complete proteome, Reference proteome
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Main funding by: National Institutes of Health