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Q6R6M4 (U17L2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 79. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Ubiquitin carboxyl-terminal hydrolase 17

Short name=USP17
EC=3.4.19.12
Alternative name(s):
Deubiquitinating enzyme 17-like protein 2
Deubiquitinating protein 3
Short name=DUB-3
Ubiquitin carboxyl-terminal hydrolase 17-like protein 2
Ubiquitin thioesterase 17-like protein 2
Ubiquitin-specific-processing protease 17-like protein 2
Gene names
Name:USP17L2
Synonyms:DUB3, USP17, USP17H, USP17I, USP17J, USP17K, USP17L, USP17M
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length530 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes. Regulates cell proliferation by deubiquitinating and inhibiting RCE1 thereby controlling the small GTPases NRAS and HRAS localization and activation. In parallel, mediates deubiquitination of CDC25A, preventing CDC25A degradation by the proteasome during the G1/S and G2/M phases promoting cell-cycle progression. Also regulates cell proliferation and apoptosis through deubiquitination of SUDS3 a regulator of histone deacetylation. Through activation of the Rho family GTPases RAC1A, CDC42 and RHOA, regulates cell migration. Through the cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains of the cytoplasmic innate immune receptors DDX58 and IFIH1 stimulates the cellular response to viral infection. Ref.1 Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12

Catalytic activity

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). Ref.1 Ref.8 Ref.10

Subunit structure

Interacts with SUDS3; the interaction is direct. Ref.11

Subcellular location

Nucleus. Endoplasmic reticulum Ref.5 Ref.11.

Tissue specificity

Broadly expressed. Ref.1

Induction

Up-regulated by IL4/interleukin-4, IL6/interleukin-6 and chemokines including CXCL8 and CXCL12 (at protein level). Up-regulated during the G1/S transition of the cell cycle. Ref.1 Ref.7 Ref.12

Miscellaneous

Overexpressed in a subset of human breast cancers, overexpression leading to an abnormally high level of CDC25A, which arrests cells through replication stress or premature mitosis, the latter occurring when CDK1 is activated inappropriately (Ref.10).

Sequence similarities

Belongs to the peptidase C19 family. USP17 subfamily.

Contains 1 USP domain.

Caution

The RS447 megasatellite DNA is a highly polymorphic conserved tandem repetitive sequence which contains a copy of the USP17 gene. It is present with an interindividual variation in copy number, ranging from 20 to 103, and can be found in the genome both on chromosome 4 and chromosome 8. USP17 is also frequently named DUB3 in the literature. The high similarity between the UPS17-like genes makes impossible to clearly assign data to one of the genes of the family. Oligonucleotides designed in RNAi experiments are for instance not specific of a given UPS17-like gene.

Ontologies

Keywords
   Biological processApoptosis
Cell cycle
Ubl conjugation pathway
   Cellular componentEndoplasmic reticulum
Nucleus
   Coding sequence diversityPolymorphism
   Molecular functionHydrolase
Protease
Thiol protease
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processCAAX-box protein processing

Inferred from mutant phenotype Ref.5. Source: UniProtKB

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

cell cycle checkpoint

Inferred from mutant phenotype Ref.10. Source: UniProtKB

mitotic cell cycle checkpoint

Inferred from mutant phenotype Ref.10. Source: UniProtKB

negative regulation of Ras GTPase activity

Inferred from direct assay Ref.5. Source: UniProtKB

negative regulation of histone deacetylation

Inferred from mutant phenotype Ref.11. Source: UniProtKB

negative regulation of protein processing

Inferred from mutant phenotype Ref.5. Source: UniProtKB

negative regulation of protein targeting to membrane

Inferred from mutant phenotype Ref.5. Source: UniProtKB

positive regulation of MDA-5 signaling pathway

Inferred from mutant phenotype Ref.8. Source: UniProtKB

positive regulation of RIG-I signaling pathway

Inferred from mutant phenotype Ref.8. Source: UniProtKB

positive regulation of Rho GTPase activity

Inferred from mutant phenotype Ref.12. Source: UniProtKB

protein K48-linked deubiquitination

Inferred from mutant phenotype Ref.5Ref.8. Source: UniProtKB

protein K63-linked deubiquitination

Inferred from direct assay Ref.11. Source: UniProtKB

protein deubiquitination

Inferred from direct assay Ref.10. Source: UniProtKB

regulation of apoptotic process

Inferred from mutant phenotype Ref.11. Source: UniProtKB

regulation of cell migration

Inferred from mutant phenotype Ref.12. Source: UniProtKB

regulation of cell proliferation

Inferred from mutant phenotype Ref.5. Source: UniProtKB

regulation of defense response to virus by host

Inferred from mutant phenotype Ref.8. Source: UniProtKB

regulation of ruffle assembly

Inferred from mutant phenotype Ref.12. Source: UniProtKB

ubiquitin-dependent protein catabolic process

Inferred from electronic annotation. Source: InterPro

   Cellular_componentendoplasmic reticulum membrane

Inferred from direct assay Ref.5. Source: UniProtKB

nucleus

Inferred from direct assay Ref.11. Source: UniProtKB

   Molecular_functionprotein binding

Inferred from physical interaction Ref.11. Source: UniProtKB

ubiquitin thiolesterase activity

Inferred from mutant phenotype Ref.10. Source: UniProtKB

ubiquitin-specific protease activity

Inferred from direct assay Ref.10Ref.11. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 530530Ubiquitin carboxyl-terminal hydrolase 17
PRO_0000331644

Regions

Domain80 – 375296USP
Region399 – 530132Mediates interaction with SUDS3

Sites

Active site891Nucleophile
Active site3341Proton acceptor By similarity

Natural variations

Natural variant4381K → R.
Corresponds to variant rs12543578 [ dbSNP | Ensembl ].
VAR_059750

Experimental info

Mutagenesis891C → S: Abolishes both enzymatic activity and effects on cell proliferation. Ref.1
Sequence conflict661K → E in AAR91701. Ref.1
Sequence conflict2141S → P in AAR91701. Ref.1
Sequence conflict3321D → N in AAR91701. Ref.1
Sequence conflict3531K → E in AAR91701. Ref.1
Sequence conflict3571C → S in AAR91701. Ref.1
Sequence conflict4231R → H in AAR91701. Ref.1
Sequence conflict4401P → L in AAR91701. Ref.1
Sequence conflict4621N → D in AAR91701. Ref.1
Sequence conflict4941R → P in AAR91701. Ref.1
Sequence conflict4961D → H in AAR91701. Ref.1
Sequence conflict5001V → M in AAR91701. Ref.1
Sequence conflict5091Q → R in AAR91701. Ref.1
Sequence conflict5121T → A in AAR91701. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q6R6M4 [UniParc].

Last modified April 29, 2008. Version 2.
Checksum: B117BB171376B0E4

FASTA53059,619
        10         20         30         40         50         60 
MEDDSLYLGG EWQFNHFSKL TSSRPDAAFA EIQRTSLPEK SPLSSEARVD LCDDLAPVAR 

        70         80         90        100        110        120 
QLAPRKKLPL SSRRPAAVGA GLQNMGNTCY ENASLQCLTY TPPLANYMLS REHSQTCQRP 

       130        140        150        160        170        180 
KCCMLCTMQA HITWALHSPG HVIQPSQALA AGFHRGKQED AHEFLMFTVD AMKKACLPGH 

       190        200        210        220        230        240 
KQVDHHSKDT TLIHQIFGGC WRSQIKCLHC HGISDTFDPY LDIALDIQAA QSVKQALEQL 

       250        260        270        280        290        300 
VKPEELNGEN AYHCGLCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK LAKNVQYPEC 

       310        320        330        340        350        360 
LDMQPYMSQQ NTGPLVYVLY AVLVHAGWSC HDGHYFSYVK AQEGQWYKMD DAKVTACSIT 

       370        380        390        400        410        420 
SVLSQQAYVL FYIQKSEWER HSESVSRGRE PRALGAEDTD RRATQGELKR DHPCLQAPEL 

       430        440        450        460        470        480 
DERLVERATQ ESTLDHWKFP QEQNKTKPEF NVRKVEGTLP PNVLVIHQSK YKCGMKNHHP 

       490        500        510        520        530 
EQQSSLLNLS STTRTDQESV NTGTLASLQG RTRRSKGKNK HSKRALLVCQ 

« Hide

References

« Hide 'large scale' references
[1]"DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks proliferation."
Burrows J.F., McGrattan M.J., Rascle A., Humbert M., Baek K.-H., Johnston J.A.
J. Biol. Chem. 279:13993-14000(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, INDUCTION BY CYTOKINES, TISSUE SPECIFICITY, MUTAGENESIS OF CYS-89.
[2]"DNA sequence and analysis of human chromosome 8."
Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., Asakawa T. expand/collapse author list , Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., Lander E.S.
Nature 439:331-335(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The DUB/USP17 deubiquitinating enzymes, a multigene family within a tandemly repeated sequence."
Burrows J.F., McGrattan M.J., Johnston J.A.
Genomics 85:524-529(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NOMENCLATURE.
[4]"Hyaluronan- and RNA-binding deubiquitinating enzymes of USP17 family members associated with cell viability."
Shin J.-M., Yoo K.-J., Kim M.-S., Kim D., Baek K.-H.
BMC Genomics 7:292-292(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NOMENCLATURE, FUNCTION IN APOPTOSIS.
[5]"USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity."
Burrows J.F., Kelvin A.A., McFarlane C., Burden R.E., McGrattan M.J., De la Vega M., Govender U., Quinn D.J., Dib K., Gadina M., Scott C.J., Johnston J.A.
J. Biol. Chem. 284:9587-9595(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL PROLIFERATION, SUBCELLULAR LOCATION.
[6]"The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly repeated sequence, is also embedded within the copy number variable beta-defensin cluster."
Burrows J.F., Scott C.J., Johnston J.A.
BMC Genomics 11:250-250(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION.
[7]"The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies, is cell cycle regulated, and is required for G1-S progression."
McFarlane C., Kelvin A.A., de la Vega M., Govender U., Scott C.J., Burrows J.F., Johnston J.A.
Cancer Res. 70:3329-3339(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
[8]"The ubiquitin-specific protease 17 is involved in virus-triggered type I IFN signaling."
Chen R., Zhang L., Zhong B., Tan B., Liu Y., Shu H.B.
Cell Res. 20:802-811(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, FUNCTION IN CELLULAR ANTIVIRAL RESPONSE.
[9]"The deubiquitinating enzyme USP17 blocks N-Ras membrane trafficking and activation but leaves K-Ras unaffected."
de la Vega M., Burrows J.F., McFarlane C., Govender U., Scott C.J., Johnston J.A.
J. Biol. Chem. 285:12028-12036(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[10]"Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A."
Pereg Y., Liu B.Y., O'Rourke K.M., Sagolla M., Dey A., Komuves L., French D.M., Dixit V.M.
Nat. Cell Biol. 12:400-406(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, FUNCTION IN CELL PROLIFERATION.
[11]"Lys-63-specific deubiquitination of SDS3 by USP17 regulates HDAC activity."
Ramakrishna S., Suresh B., Lee E.J., Lee H.J., Ahn W.S., Baek K.H.
J. Biol. Chem. 286:10505-10514(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SUDS3, SUBCELLULAR LOCATION.
[12]"The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility."
de la Vega M., Kelvin A.A., Dunican D.J., McFarlane C., Burrows J.F., Jaworski J., Stevenson N.J., Dib K., Rappoport J.Z., Scott C.J., Long A., Johnston J.A.
Nat. Commun. 2:259-259(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION, INDUCTION BY CHEMOKINE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY509884 mRNA. Translation: AAR91701.1.
AC130366 Genomic DNA. No translation available.
CCDSCCDS43713.1.
RefSeqNP_958804.2. NM_201402.2.
UniGeneHs.531448.

3D structure databases

ProteinModelPortalQ6R6M4.
SMRQ6R6M4. Positions 49-372.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid132019. 5 interactions.
IntActQ6R6M4. 4 interactions.
STRING9606.ENSP00000333329.

Protein family/group databases

MEROPSC19.023.

Polymorphism databases

DMDM187663988.

Proteomic databases

PaxDbQ6R6M4.
PRIDEQ6R6M4.

Protocols and materials databases

DNASU377630.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000333796; ENSP00000333329; ENSG00000223443.
GeneID377630.
KEGGhsa:377630.
UCSCuc003wvc.1. human.

Organism-specific databases

CTD377630.
GeneCardsGC08M011994.
H-InvDBHIX0034323.
HGNCHGNC:34434. USP17L2.
HPAHPA045642.
MIM610186. gene.
neXtProtNX_Q6R6M4.
PharmGKBPA165586023.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5533.
HOGENOMHOG000144638.
HOVERGENHBG007129.
InParanoidQ6R6M4.
KOK11845.
OMARACDITS.
OrthoDBEOG73NG35.
PhylomeDBQ6R6M4.
TreeFamTF315281.

Gene expression databases

GenevestigatorQ6R6M4.

Family and domain databases

InterProIPR006861. HABP4_PAIRBP1-bd.
IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19_UCH.
IPR028889. UCH/PAN2.
[Graphical view]
PfamPF04774. HABP4_PAI-RBP1. 1 hit.
PF00443. UCH. 1 hit.
[Graphical view]
PROSITEPS00973. USP_2. 1 hit.
PS50235. USP_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GenomeRNAi377630.
NextBio100679.
PROQ6R6M4.
SOURCESearch...

Entry information

Entry nameU17L2_HUMAN
AccessionPrimary (citable) accession number: Q6R6M4
Entry history
Integrated into UniProtKB/Swiss-Prot: April 29, 2008
Last sequence update: April 29, 2008
Last modified: July 9, 2014
This is version 79 of the entry and version 2 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

Peptidase families

Classification of peptidase families and list of entries

MIM cross-references

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

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 8

Human chromosome 8: entries, gene names and cross-references to MIM