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Q8WZ73 (RFFL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 116. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase rififylin

EC=6.3.2.-
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
Gene names
Name:RFFL
Synonyms:RNF189, RNF34L
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length363 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Also ubiquitinates the caspases CASP8 and CASP10, promoting their proteasomal degradation, to negatively regulate apoptosis downstream of death domain receptors. Also 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 SNF. May also play a role in endocytic recycling. Ref.7 Ref.8 Ref.9 Ref.10 Ref.12

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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. Ref.7 Ref.8 Ref.9 Ref.10 Ref.12

Subcellular location

Cytoplasmcytosol. Cell membrane; Peripheral membrane protein. Recycling endosome membrane; Peripheral membrane protein By similarity. Note: The FYVE-type zinc finger may mediate phosphatidylinositol phosphate-binding and control subcellular localization. Ref.7 Ref.10

Tissue specificity

Ubiquitous. Detected in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. Ref.7

Induction

Down-regulated upon DNA damage. Ref.9

Domain

The RING-type zinc finger is required for target protein ubiquitination.

The FYVE-type zinc finger domain is required for localization to the recycling endosome membranes and the function in endocytic recycling By similarity.

Post-translational modification

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.

Sequence similarities

Contains 1 FYVE-type zinc finger.

Contains 1 RING-type zinc finger.

Contains 2 SAP domains.

Ontologies

Keywords
   Biological processApoptosis
Ubl conjugation pathway
   Cellular componentCell membrane
Cytoplasm
Endosome
Membrane
   Coding sequence diversityAlternative splicing
   DomainRepeat
Zinc-finger
   LigandMetal-binding
Zinc
   Molecular functionLigase
   PTMLipoprotein
Palmitate
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processintracellular protein transport

Inferred from electronic annotation. Source: Ensembl

negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis

Inferred from mutant phenotype Ref.7. Source: UniProtKB

negative regulation of extrinsic apoptotic signaling pathway via death domain receptors

Inferred from mutant phenotype Ref.7. Source: UniProtKB

negative regulation of signal transduction by p53 class mediator

Inferred from mutant phenotype Ref.8. Source: UniProtKB

negative regulation of tumor necrosis factor-mediated signaling pathway

Inferred from mutant phenotype Ref.10. Source: UniProtKB

proteasome-mediated ubiquitin-dependent protein catabolic process

Inferred from mutant phenotype Ref.9Ref.12. Source: UniProtKB

protein K48-linked ubiquitination

Inferred from direct assay Ref.10Ref.12. Source: UniProtKB

regulation of TOR signaling

Inferred by curator Ref.12. Source: UniProtKB

regulation of fibroblast migration

Inferred from sequence or structural similarity. Source: UniProtKB

ubiquitin-dependent protein catabolic process

Inferred from direct assay Ref.7. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from direct assay Ref.7. Source: UniProtKB

cytoplasmic membrane-bounded vesicle

Inferred from electronic annotation. Source: Ensembl

cytosol

Inferred from electronic annotation. Source: UniProtKB-SubCell

endosome membrane

Inferred from direct assay Ref.10. Source: UniProtKB

plasma membrane

Inferred from direct assay Ref.7. Source: UniProtKB

recycling endosome membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionp53 binding

Inferred from physical interaction Ref.8Ref.9. Source: UniProtKB

protease binding

Inferred from physical interaction Ref.7. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.12. Source: UniProtKB

protein kinase binding

Inferred from physical interaction Ref.10. Source: UniProtKB

ubiquitin protein ligase binding

Inferred from physical interaction Ref.9. Source: UniProtKB

ubiquitin-protein transferase activity

Inferred from direct assay Ref.8Ref.12. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q8WZ73-1)

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: Q8WZ73-2)

The sequence of this isoform differs from the canonical sequence as follows:
     296-303: Missing.
Isoform 3 (identifier: Q8WZ73-3)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 363363E3 ubiquitin-protein ligase rififylin
PRO_0000056025

Regions

Domain101 – 12020SAP 1
Domain250 – 26415SAP 2
Zinc finger41 – 9656FYVE-type
Zinc finger316 – 35136RING-type

Amino acid modifications

Modified residue2261Phosphoserine Ref.11
Modified residue2291Phosphoserine Ref.11

Natural variations

Alternative sequence197 – 22428Missing in isoform 3.
VSP_015751
Alternative sequence296 – 3038Missing in isoform 2 and isoform 3.
VSP_015752

Experimental info

Mutagenesis3331H → A: Loss of E3 ubiquitin protein ligase activity. Ref.7
Sequence conflict1271E → G in AAH28424. Ref.6

Secondary structure

.................. 363
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified March 1, 2002. Version 1.
Checksum: 9456ED5A0503AFFB

FASTA36340,514
        10         20         30         40         50         60 
MWATCCNWFC LDGQPEEVPP PQGARMQAYS NPGYSSFPSP TGLEPSCKSC GAHFANTARK 

        70         80         90        100        110        120 
QTCLDCKKNF CMTCSSQVGN GPRLCLLCQR FRATAFQREE LMKMKVKDLR DYLSLHDIST 

       130        140        150        160        170        180 
EMCREKEELV LLVLGQQPVI SQEDRTRAST LSPDFPEQQA FLTQPHSSMV PPTSPNLPSS 

       190        200        210        220        230        240 
SAQATSVPPA QVQENQQANG HVSQDQEEPV YLESVARVPA EDETQSIDSE DSFVPGRRAS 

       250        260        270        280        290        300 
LSDLTDLEDI EGLTVRQLKE ILARNFVNYK GCCEKWELME RVTRLYKDQK GLQHLVSGAE 

       310        320        330        340        350        360 
DQNGGAVPSG LEENLCKICM DSPIDCVLLE CGHMVTCTKC GKRMNECPIC RQYVIRAVHV 


FRS 

« Hide

Isoform 2 [UniParc].

Checksum: 0F22B82AD059DE03
Show »

FASTA35539,713
Isoform 3 [UniParc].

Checksum: 34CE0CD40417BE8E
Show »

FASTA32736,633

References

« Hide 'large scale' references
[1]"Fring, a protein with a modified FYVE domain and a ring domain."
Hong W.
Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]Kanbe D., Araki K., Nawa H.
Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Testis.
[4]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Testis carcinoma.
[5]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. expand/collapse author list , 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].
[6]"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 3).
Tissue: Testis.
[7]"Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth."
McDonald E.R. III, El-Deiry W.S.
Proc. Natl. Acad. Sci. U.S.A. 101:6170-6175(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN APOPTOSIS, INTERACTION WITH CASP8 AND CASP10, MUTAGENESIS OF HIS-333, PROTEOLYTIC DEGRADATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[8]"CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation."
Yang W., Rozan L.M., McDonald E.R. III, Navaraj A., Liu J.J., Matthew E.M., Wang W., Dicker D.T., El-Deiry W.S.
J. Biol. Chem. 282:3273-3281(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN P53/TP53 UBIQUITINATION, INTERACTION WITH P53/TP53.
[9]"CARPs enhance p53 turnover by degrading 14-3-3sigma and stabilizing MDM2."
Yang W., Dicker D.T., Chen J., El-Deiry W.S.
Cell Cycle 7:670-682(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN UBIQUITINATION OF SFN, INTERACTION WITH MDM2 AND P53/TP53, INDUCTION.
[10]"CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation."
Liao W., Xiao Q., Tchikov V., Fujita K., Yang W., Wincovitch S., Garfield S., Conze D., El-Deiry W.S., Schuetze S., Srinivasula S.M.
Curr. Biol. 18:641-649(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN TNF SIGNALING, INTERACTION WITH RIPK1, SUBCELLULAR LOCATION.
[11]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-226 AND SER-229, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[12]"PRR5L degradation promotes mTORC2-mediated PKC-delta phosphorylation and cell migration downstream of Galpha12."
Gan X., Wang J., Wang C., Sommer E., Kozasa T., Srinivasula S., Alessi D., Offermanns S., Simon M.I., Wu D.
Nat. Cell Biol. 14:686-696(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN UBIQUITINATION OF PRR5L, INTERACTION WITH PRR5L AND THE MTORC2 COMPLEX.
[13]"Crystal structure of a FYVE-type zinc finger domain from the caspase regulator CARP2."
Tibbetts M.D., Shiozaki E.N., Gu L., McDonald E.R. III, El-Deiry W.S., Shi Y.
Structure 12:2257-2263(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 26-145.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS11286.1. [Q8WZ73-1]
RefSeqNP_001017368.1. NM_001017368.1. [Q8WZ73-1]
UniGeneHs.13680.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1Y02X-ray1.80A26-145[»]
ProteinModelPortalQ8WZ73.
SMRQ8WZ73. Positions 45-139, 275-361.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid125593. 17 interactions.
IntActQ8WZ73. 2 interactions.
STRING9606.ENSP00000326170.

PTM databases

PhosphoSiteQ8WZ73.

Polymorphism databases

DMDM74760639.

Proteomic databases

MaxQBQ8WZ73.
PaxDbQ8WZ73.
PRIDEQ8WZ73.

Protocols and materials databases

DNASU117584.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000268850; ENSP00000268850; ENSG00000092871. [Q8WZ73-3]
ENST00000315249; ENSP00000326170; ENSG00000092871. [Q8WZ73-1]
ENST00000378516; ENSP00000367777; ENSG00000092871. [Q8WZ73-2]
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]
GeneID117584.
KEGGhsa:117584.
UCSCuc002him.1. human. [Q8WZ73-2]
uc002hin.1. human. [Q8WZ73-1]
uc002hip.2. human. [Q8WZ73-3]

Organism-specific databases

CTD117584.
GeneCardsGC17M033333.
HGNCHGNC:24821. RFFL.
HPACAB008096.
HPA017910.
HPA019492.
MIM609735. gene.
neXtProtNX_Q8WZ73.
PharmGKBPA142671086.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG121302.
HOGENOMHOG000068080.
HOVERGENHBG055079.
InParanoidQ8WZ73.
OMAHQQANGH.
OrthoDBEOG70GMFS.
PhylomeDBQ8WZ73.
TreeFamTF325195.

Enzyme and pathway databases

UniPathwayUPA00143.

Gene expression databases

ArrayExpressQ8WZ73.
BgeeQ8WZ73.
CleanExHS_RFFL.
GenevestigatorQ8WZ73.

Family and domain databases

Gene3D3.30.40.10. 2 hits.
InterProIPR011011. Znf_FYVE_PHD.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]
SMARTSM00184. RING. 1 hit.
[Graphical view]
SUPFAMSSF57903. SSF57903. 1 hit.
PROSITEPS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ8WZ73.
GeneWikiRFFL.
GenomeRNAi117584.
NextBio80230.
PROQ8WZ73.
SOURCESearch...

Entry information

Entry nameRFFL_HUMAN
AccessionPrimary (citable) accession number: Q8WZ73
Secondary accession number(s): E1P633 expand/collapse secondary AC list , Q8NHW0, Q8TBY7, Q96BE6
Entry history
Integrated into UniProtKB/Swiss-Prot: September 27, 2005
Last sequence update: March 1, 2002
Last modified: July 9, 2014
This is version 116 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM