UBP2_RAT
ID UBP2_RAT Reviewed; 618 AA.
AC Q5U349; Q9QXL3; Q9QXL4; Q9R083; Q9R084;
DT 10-AUG-2010, integrated into UniProtKB/Swiss-Prot.
DT 07-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 117.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 2;
DE EC=3.4.19.12;
DE AltName: Full=41 kDa ubiquitin-specific protease;
DE AltName: Full=Deubiquitinating enzyme 2;
DE AltName: Full=Ubiquitin thioesterase 2;
DE AltName: Full=Ubiquitin-specific-processing protease 2;
DE AltName: Full=Ubiquitin-specific-processing protease testis;
DE Short=UBP-t;
GN Name=Usp2; Synonyms=Ubp41, Ubp69;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, ACTIVITY
RP REGULATION, AND TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=10938131; DOI=10.1128/mcb.20.17.6568-6578.2000;
RA Lin H., Keriel A., Morales C.R., Bedard N., Zhao Q., Hingamp P.,
RA Lefrancois S., Combaret L., Wing S.S.;
RT "Divergent N-terminal sequences target an inducible testis deubiquitinating
RT enzyme to distinct subcellular structures.";
RL Mol. Cell. Biol. 20:6568-6578(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, SUBCELLULAR
RP LOCATION, INDUCTION, MUTAGENESIS OF CYS-289, TISSUE SPECIFICITY, AND
RP DOMAIN.
RC TISSUE=Skeletal muscle;
RX PubMed=12107281; DOI=10.1073/pnas.152011799;
RA Park K.C., Kim J.H., Choi E.J., Min S.W., Rhee S., Baek S.H., Chung S.S.,
RA Bang O., Park D., Chiba T., Tanaka K., Chung C.H.;
RT "Antagonistic regulation of myogenesis by two deubiquitinating enzymes,
RT UBP45 and UBP69.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:9733-9738(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP TISSUE SPECIFICITY, AND INDUCTION BY IL-1.
RX PubMed=20403044; DOI=10.1111/j.1440-1827.2010.02496.x;
RA Wang S., Wu H., Liu Y., Sun J., Zhao Z., Chen Q., Guo M., Ma D., Zhang Z.;
RT "Expression of USP2-69 in mesangial cells in vivo and in vitro.";
RL Pathol. Int. 60:184-192(2010).
RN [6]
RP FUNCTION, AND INTERACTION WITH PER1.
RX PubMed=23213472; DOI=10.1242/bio.20121990;
RA Yang Y., Duguay D., Bedard N., Rachalski A., Baquiran G., Na C.H.,
RA Fahrenkrug J., Storch K.F., Peng J., Wing S.S., Cermakian N.;
RT "Regulation of behavioral circadian rhythms and clock protein PER1 by the
RT deubiquitinating enzyme USP2.";
RL Biol. Open 1:789-801(2012).
CC -!- FUNCTION: Hydrolase that deubiquitinates polyubiquitinated target
CC proteins such as MDM2, MDM4 and CCND1 (By similarity). Isoform 1 and
CC isoform 2 possess both ubiquitin-specific peptidase and isopeptidase
CC activities (PubMed:12107281). Deubiquitinates MDM2 without reversing
CC MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes
CC p53/TP53 degradation and limits p53 activity (By similarity). Has no
CC deubiquitinase activity against p53/TP53 (By similarity). Prevents
CC MDM2-mediated degradation of MDM4 (By similarity). Plays a role in the
CC G1/S cell-cycle progression in normal and cancer cells (By similarity).
CC Regulates the circadian clock by modulating its intrinsic circadian
CC rhythm and its capacity to respond to external cues (PubMed:23213472).
CC Associates with clock proteins and deubiquitinates core clock component
CC PER1 but does not affect its overall stability (PubMed:23213472).
CC Regulates the nucleocytoplasmic shuttling and nuclear retention of PER1
CC and its repressive role on the clock transcription factors CLOCK and
CC ARNTL/BMAL1 (By similarity). Plays a role in the regulation of myogenic
CC differentiation of embryonic muscle cells (PubMed:12107281).
CC {ECO:0000250|UniProtKB:O75604, ECO:0000250|UniProtKB:O88623,
CC ECO:0000269|PubMed:10938131, ECO:0000269|PubMed:12107281,
CC ECO:0000269|PubMed:23213472}.
CC -!- FUNCTION: [Isoform 2]: Circadian clock output effector that regulates
CC Ca(2+) absorption in the small intestine. Probably functions by
CC regulating protein levels of the membrane scaffold protein NHERF4 in a
CC rhythmic manner, and is therefore likely to control Ca(2+) membrane
CC permeability mediated by the Ca(2+) channel TRPV6 in the intestine.
CC {ECO:0000250|UniProtKB:O88623}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12;
CC -!- ACTIVITY REGULATION: Cleavage is inhibited by ubiquitin in a dosage-
CC dependent manner (By similarity). Cleavage is blocked by ubiquitin
CC aldehyde. {ECO:0000250|UniProtKB:O75604, ECO:0000269|PubMed:10938131}.
CC -!- SUBUNIT: Homooligomer. Found in trimeric complex with MDM2 and MDM4 and
CC USP2. Interacts with CCND1; the interaction is direct and promotes its
CC stabilization by antagonizing ubiquitin-dependent degradation.
CC Interacts (via N-terminus and C-terminus) with MDM2. Interacts with
CC MDM4 (By similarity). Interacts with PER1. Interacts with KCNQ1;
CC counteracts the NEDD4L-specific down-regulation of I(Ks) and restores
CC plasma membrane localization of KCNQ1 (By similarity). Isoform 4:
CC Interacts with PDZD3 and CLTC (By similarity).
CC {ECO:0000250|UniProtKB:O75604, ECO:0000250|UniProtKB:O88623,
CC ECO:0000269|PubMed:23213472}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O88623}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:12107281}. Note=Localizes in the spermatid head in
CC late-elongating spermatids in the thin area between the outer acrosomal
CC membrane and the plasma membrane. {ECO:0000269|PubMed:12107281}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus
CC {ECO:0000269|PubMed:12107281}. Membrane {ECO:0000250|UniProtKB:O88623};
CC Peripheral membrane protein {ECO:0000305}. Cytoplasm
CC {ECO:0000250|UniProtKB:O88623}. Note=Predominantly expressed at
CC membranes. {ECO:0000250|UniProtKB:O88623}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Ubp69, Ubp-t2;
CC IsoId=Q5U349-1; Sequence=Displayed;
CC Name=2; Synonyms=Ubp45, Ubp-t1;
CC IsoId=Q5U349-2; Sequence=VSP_039561;
CC -!- TISSUE SPECIFICITY: Expressed in mesangial cells of the kidney. Isoform
CC 1 and isoform 2 are expressed in elongated spermatids; the shorter form
CC appearing earlier than the longer form (at protein level). Isoform 1
CC and isoform 2 are expressed in early round spermatids of the testis.
CC Isoform 1 is expressed in muscle and heart. Isoform 2 is expressed in
CC muscle, lung, heart, brain, liver and ovary. During muscle
CC differentiation, isoform 1 expression increases before the onset of
CC membrane fusion and decreases as the myogenic processes proceeded; un
CC counterpart, isoform 2 expression remains low until the burst of
CC membrane fusion but increases thereafter. {ECO:0000269|PubMed:10938131,
CC ECO:0000269|PubMed:12107281, ECO:0000269|PubMed:20403044}.
CC -!- INDUCTION: Up-regulated by IL-1. Isoform 1 is up-regulated with any
CC signal for withdrawal from the cell cycle such as serum deprivation.
CC {ECO:0000269|PubMed:12107281, ECO:0000269|PubMed:20403044}.
CC -!- DOMAIN: The different N-terminus extensions of isoform 1 and isoform 2
CC determine their respective subcellular localization and differentiel
CC effect on myoblast fusion and accumulation of muscle-specific proteins.
CC The different N-terminus extensions of isoform 1 and isoform 2 are not
CC essential for their catalytic activity. {ECO:0000269|PubMed:12107281}.
CC -!- MISCELLANEOUS: [Isoform 1]: Stimulates both membrane fusion during
CC myogenesis and accumulation of muscle-specific proteins.
CC -!- MISCELLANEOUS: [Isoform 2]: Inhibits both membrane fusion during
CC myogenesis and accumulation of muscle-specific proteins. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. USP2 subfamily.
CC {ECO:0000305}.
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DR EMBL; AF202453; AAF17574.1; -; mRNA.
DR EMBL; AF202454; AAF17575.1; -; mRNA.
DR EMBL; AF106658; AAF14189.1; -; mRNA.
DR EMBL; AF106659; AAF14190.1; -; mRNA.
DR EMBL; CH473975; EDL95274.1; -; Genomic_DNA.
DR EMBL; CH473975; EDL95276.1; -; Genomic_DNA.
DR EMBL; CH473975; EDL95277.1; -; Genomic_DNA.
DR EMBL; BC085719; AAH85719.1; -; mRNA.
DR RefSeq; NP_446226.2; NM_053774.2. [Q5U349-1]
DR RefSeq; XP_006242923.1; XM_006242861.3. [Q5U349-1]
DR RefSeq; XP_006242925.1; XM_006242863.3. [Q5U349-2]
DR AlphaFoldDB; Q5U349; -.
DR SMR; Q5U349; -.
DR BioGRID; 250433; 2.
DR DIP; DIP-48683N; -.
DR IntAct; Q5U349; 1.
DR STRING; 10116.ENSRNOP00000009975; -.
DR MEROPS; C19.013; -.
DR PaxDb; Q5U349; -.
DR Ensembl; ENSRNOT00000036051; ENSRNOP00000030257; ENSRNOG00000006663. [Q5U349-2]
DR Ensembl; ENSRNOT00000104911; ENSRNOP00000078529; ENSRNOG00000006663. [Q5U349-1]
DR GeneID; 115771; -.
DR KEGG; rno:115771; -.
DR UCSC; RGD:621073; rat. [Q5U349-1]
DR CTD; 9099; -.
DR RGD; 621073; Usp2.
DR eggNOG; KOG1868; Eukaryota.
DR GeneTree; ENSGT00940000161289; -.
DR HOGENOM; CLU_008279_1_2_1; -.
DR InParanoid; Q5U349; -.
DR OMA; KYWVKYL; -.
DR OrthoDB; 1283205at2759; -.
DR PhylomeDB; Q5U349; -.
DR TreeFam; TF106277; -.
DR Reactome; R-RNO-5357786; TNFR1-induced proapoptotic signaling.
DR Reactome; R-RNO-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-RNO-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR Reactome; R-RNO-6804757; Regulation of TP53 Degradation.
DR PRO; PR:Q5U349; -.
DR Proteomes; UP000002494; Chromosome 8.
DR Proteomes; UP000234681; Chromosome 8.
DR Bgee; ENSRNOG00000006663; Expressed in testis and 19 other tissues.
DR Genevisible; Q5U349; RN.
DR GO; GO:0005813; C:centrosome; IDA:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0030332; F:cyclin binding; ISO:RGD.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IMP:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0048512; P:circadian behavior; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB.
DR GO; GO:0045475; P:locomotor rhythm; ISS:UniProtKB.
DR GO; GO:0007517; P:muscle organ development; IEA:UniProtKB-KW.
DR GO; GO:0051926; P:negative regulation of calcium ion transport; ISO:RGD.
DR GO; GO:0048642; P:negative regulation of skeletal muscle tissue development; IDA:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001394; Peptidase_C19_UCH.
DR InterPro; IPR018200; USP_CS.
DR InterPro; IPR028889; USP_dom.
DR Pfam; PF00443; UCH; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS00972; USP_1; 1.
DR PROSITE; PS00973; USP_2; 1.
DR PROSITE; PS50235; USP_3; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Biological rhythms; Cell cycle; Cytoplasm; Hydrolase;
KW Membrane; Metal-binding; Myogenesis; Nucleus; Protease; Reference proteome;
KW Thiol protease; Ubl conjugation pathway; Zinc.
FT CHAIN 1..618
FT /note="Ubiquitin carboxyl-terminal hydrolase 2"
FT /id="PRO_0000395966"
FT DOMAIN 280..612
FT /note="USP"
FT REGION 1..213
FT /note="Necessary for interaction with MDM4"
FT /evidence="ECO:0000250|UniProtKB:O75604"
FT REGION 54..112
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 246..274
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 416..516
FT /note="Necessary for interaction with MDM4"
FT /evidence="ECO:0000250|UniProtKB:O75604"
FT COMPBIAS 87..112
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 254..274
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 289
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT ACT_SITE 570
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT BINDING 438
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O75604"
FT BINDING 441
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O75604"
FT BINDING 489
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O75604"
FT BINDING 492
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O75604"
FT VAR_SEQ 1..271
FT /note="MSQLSSTLKRYTESSRYTDAPYAKSGYGTYTPSSYGANLAASFLEKEKLGFK
FT PVSPTSFLPRPRTYGPSSILDCDRGRPLLRSDITGGSKRSESQTRGNERPSGSGLNGGS
FT GFPYGVTSNSLSYLPMNARDQGVTLGQKKSNSQSDLARDFSSLRTSDSYRTSDGYRASD
FT GFRIDPGNLGRSPMLARTRKELCALQGLYQAASRSEYLTDYLENYGRKGSAPQVLTQAP
FT PSRVPEVLSPTYRPSGRYTLWEKNKGQASGPSRSTSPGRDTM -> MRTSYTVTLPEEP
FT PAAPFPALAKELRPRSPLSPSLLLSTFVGLLLNKAK (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10938131,
FT ECO:0000303|PubMed:12107281"
FT /id="VSP_039561"
FT MUTAGEN 289
FT /note="C->S: Loss of enzymatic activity. Reduces both
FT membrane fusion during myogenesis and accumulation of
FT muscle-specific proteins."
FT /evidence="ECO:0000269|PubMed:12107281"
FT CONFLICT 172
FT /note="F -> S (in Ref. 1; AAF17574)"
FT /evidence="ECO:0000305"
FT CONFLICT 202
FT /note="A -> T (in Ref. 2; AAF14190)"
FT /evidence="ECO:0000305"
FT CONFLICT 260
FT /note="P -> A (in Ref. 1; AAF17574)"
FT /evidence="ECO:0000305"
FT CONFLICT 607
FT /note="L -> F (in Ref. 2; AAF14189/AAF14190)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 618 AA; 69363 MW; B8B2091192CA4944 CRC64;
MSQLSSTLKR YTESSRYTDA PYAKSGYGTY TPSSYGANLA ASFLEKEKLG FKPVSPTSFL
PRPRTYGPSS ILDCDRGRPL LRSDITGGSK RSESQTRGNE RPSGSGLNGG SGFPYGVTSN
SLSYLPMNAR DQGVTLGQKK SNSQSDLARD FSSLRTSDSY RTSDGYRASD GFRIDPGNLG
RSPMLARTRK ELCALQGLYQ AASRSEYLTD YLENYGRKGS APQVLTQAPP SRVPEVLSPT
YRPSGRYTLW EKNKGQASGP SRSTSPGRDT MNSKSAQGLA GLRNLGNTCF MNSILQCLSN
TRELRDYCLQ RLYMRDLGHT SSAHTALMEE FAKLIQTIWT SSPNDVVSPS EFKTQIQRYA
PRFVGYNQQD AQEFLRFLLD GLHNEVNRVA ARPKPSPESL DHLPDEEKGR QMWRKYLERE
DSRIGDLFVG QLKSSLTCTD CGYCSTVFDP FWDLSLPIAK RGYPEVTLMD CMRLFTKEDV
LDGDEKPTCC RCRARKRCIK KFSVQRFPKI LVLHLKRFSE SRIRTSKLTT FVNFPLRDLD
LREFASENTN HAVYNLYAVS NHSGTTMGGH YTAYCRSPVT GEWHTFNDSS VTPMSSSQVR
TSDAYLLFYE LASPPSRM
