Full text data of UCHL3
UCHL3
[Confidence: low (only semi-automatic identification from reviews)]
Ubiquitin carboxyl-terminal hydrolase isozyme L3; UCH-L3; 3.4.19.12 (Ubiquitin thioesterase L3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ubiquitin carboxyl-terminal hydrolase isozyme L3; UCH-L3; 3.4.19.12 (Ubiquitin thioesterase L3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P15374
ID UCHL3_HUMAN Reviewed; 230 AA.
AC P15374; B2R970; Q5TBK8; Q6IBE9;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L3;
DE Short=UCH-L3;
DE EC=3.4.19.12;
DE AltName: Full=Ubiquitin thioesterase L3;
GN Name=UCHL3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=2530630; DOI=10.1126/science.2530630;
RA Wilkinson K.D., Lee K., Deshpande S., Duerksen-Hughes P., Boss J.M.,
RA Pohl J.;
RT "The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal
RT hydrolase.";
RL Science 246:670-673(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, ENZYME ACTIVITY, TISSUE SPECIFICITY, AND MUTAGENESIS OF
RP CYS-95.
RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532;
RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.;
RT "Cleavage of the C-terminus of NEDD8 by UCH-L3.";
RL Biochem. Biophys. Res. Commun. 251:688-692(1998).
RN [9]
RP IDENTIFICATION AS TUMOR-ASSOCIATED ANTIGEN BY MASS SPECTROMETRY.
RX PubMed=14595809; DOI=10.1002/pmic.200300594;
RA Nam M.J., Madoz-Gurpide J., Wang H., Lescure P., Schmalbach C.E.,
RA Zhao R., Misek D.E., Kuick R., Brenner D.E., Hanash S.M.;
RT "Molecular profiling of the immune response in colon cancer using
RT protein microarrays: occurrence of autoantibodies to ubiquitin C-
RT terminal hydrolase L3.";
RL Proteomics 3:2108-2115(2003).
RN [10]
RP SUBSTRATE SPECIFICITY.
RX PubMed=15157086; DOI=10.1021/bi049722j;
RA Mason D.E., Ek J., Peters E.C., Harris J.L.;
RT "Substrate profiling of deubiquitin hydrolases with a positional
RT scanning library and mass spectrometry.";
RL Biochemistry 43:6535-6544(2004).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-130, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH UBIQUITIN,
RP FUNCTION, ENZYME REGULATION, AND MUTAGENESIS OF ASP-33 AND CYS-95.
RX PubMed=19154770; DOI=10.1016/j.neuint.2008.12.013;
RA Setsuie R., Sakurai M., Sakaguchi Y., Wada K.;
RT "Ubiquitin dimers control the hydrolase activity of UCH-L3.";
RL Neurochem. Int. 54:314-321(2009).
RN [14]
RP ENZYME ACTIVITY, AND MUTAGENESIS OF ASP-33 AND CYS-95.
RX PubMed=20380862; DOI=10.1016/j.neuint.2010.03.021;
RA Setsuie R., Suzuki M., Tsuchiya Y., Wada K.;
RT "Skeletal muscles of Uchl3 knockout mice show polyubiquitinated
RT protein accumulation and stress responses.";
RL Neurochem. Int. 56:911-918(2010).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP FUNCTION.
RX PubMed=21762696; DOI=10.1016/j.febslet.2011.06.037;
RA Dennissen F.J., Kholod N., Hermes D.J., Kemmerling N.,
RA Steinbusch H.W., Dantuma N.P., van Leeuwen F.W.;
RT "Mutant ubiquitin (UBB(+1)) associated with neurodegenerative
RT disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-
RT L3).";
RL FEBS Lett. 585:2568-2574(2011).
RN [17]
RP FUNCTION, AND LINKAGE SPECIFICITY.
RX PubMed=22689415; DOI=10.1002/cbic.201200261;
RA Iphofer A., Kummer A., Nimtz M., Ritter A., Arnold T., Frank R.,
RA van den Heuvel J., Kessler B.M., Jansch L., Franke R.;
RT "Profiling ubiquitin linkage specificities of deubiquitinating enzymes
RT with branched ubiquitin isopeptide probes.";
RL ChemBioChem 13:1416-1420(2012).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=9233788; DOI=10.1093/emboj/16.13.3787;
RA Johnston S.C., Larsen C.N., Cook W.J., Wilkinson K.D., Hill C.P.;
RT "Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8-
RT A resolution.";
RL EMBO J. 16:3787-3796(1997).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) IN COMPLEX WITH UBIQUITIN
RP VINYLMETHYLESTER, AND ENZYME ACTIVITY.
RX PubMed=15531586; DOI=10.1074/jbc.M410770200;
RA Misaghi S., Galardy P.J., Meester W.J.N., Ovaa H., Ploegh H.L.,
RA Gaudet R.;
RT "Structure of the ubiquitin hydrolase UCH-L3 complexed with a suicide
RT substrate.";
RL J. Biol. Chem. 280:1512-1520(2005).
CC -!- FUNCTION: Deubiquitinating enzyme (DUB) that controls levels of
CC cellular ubiquitin through processing of ubiquitin precursors and
CC ubiquitinated proteins. Thiol protease that recognizes and
CC hydrolyzes a peptide bond at the C-terminal glycine of either
CC ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at
CC position P3", and exhibits a preference towards 'Lys-48'-linked
CC Ubiquitin chains. Deubiquitinates ENAC in apical compartments,
CC thereby regulating apical membrane recycling. Indirectly increases
CC the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-
CC signaling and insulin-induced adipogenesis. Required for stress-
CC response retinal, skeletal muscle and germ cell maintenance. May
CC be involved in working memory. Can hydrolyze UBB(+1), a mutated
CC form of ubiquitin which is not effectively degraded by the
CC proteasome and is associated with neurogenerative disorders.
CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester,
CC thioester, amide, peptide and isopeptide bonds formed by the C-
CC terminal Gly of ubiquitin (a 76-residue protein attached to
CC proteins as an intracellular targeting signal).
CC -!- ENZYME REGULATION: Inhibited by monoubiquitin and diubiquitin.
CC -!- SUBUNIT: Preferentially binds diubiquitin; the interaction does
CC not hydrolyze diubiquitin but, in vitro, inhibits the hydrolyzing
CC activity on other substrates.
CC -!- INTERACTION:
CC Q15797:SMAD1; NbExp=2; IntAct=EBI-954554, EBI-1567153;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Highly expressed in heart, skeletal muscle,
CC and testis.
CC -!- MISCELLANEOUS: Identified as a tumor-specific antigen in colon
CC cancer.
CC -!- SIMILARITY: Belongs to the peptidase C12 family.
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DR EMBL; M30496; AAA36791.1; -; mRNA.
DR EMBL; BT019359; AAV38166.1; -; mRNA.
DR EMBL; CR456855; CAG33136.1; -; mRNA.
DR EMBL; AK313665; BAG36417.1; -; mRNA.
DR EMBL; AL137244; CAI12419.1; -; Genomic_DNA.
DR EMBL; CH471093; EAW80542.1; -; Genomic_DNA.
DR EMBL; BC018125; AAH18125.1; -; mRNA.
DR PIR; A40085; A40085.
DR RefSeq; NP_001257881.1; NM_001270952.1.
DR RefSeq; NP_005993.1; NM_006002.4.
DR UniGene; Hs.162241; -.
DR PDB; 1UCH; X-ray; 1.80 A; A=1-230.
DR PDB; 1XD3; X-ray; 1.45 A; A/C=1-230.
DR PDBsum; 1UCH; -.
DR PDBsum; 1XD3; -.
DR ProteinModelPortal; P15374; -.
DR SMR; P15374; 2-230.
DR DIP; DIP-29135N; -.
DR IntAct; P15374; 10.
DR MINT; MINT-2863935; -.
DR STRING; 9606.ENSP00000366819; -.
DR BindingDB; P15374; -.
DR ChEMBL; CHEMBL6195; -.
DR MEROPS; C12.003; -.
DR PhosphoSite; P15374; -.
DR DMDM; 136682; -.
DR OGP; P15374; -.
DR REPRODUCTION-2DPAGE; IPI00011250; -.
DR PaxDb; P15374; -.
DR PeptideAtlas; P15374; -.
DR PRIDE; P15374; -.
DR DNASU; 7347; -.
DR Ensembl; ENST00000377595; ENSP00000366819; ENSG00000118939.
DR GeneID; 7347; -.
DR KEGG; hsa:7347; -.
DR UCSC; uc001vjq.4; human.
DR CTD; 7347; -.
DR GeneCards; GC13P076123; -.
DR HGNC; HGNC:12515; UCHL3.
DR HPA; HPA019678; -.
DR MIM; 603090; gene.
DR neXtProt; NX_P15374; -.
DR PharmGKB; PA37162; -.
DR eggNOG; NOG327708; -.
DR HOGENOM; HOG000182400; -.
DR HOVERGEN; HBG075483; -.
DR KO; K05609; -.
DR OMA; VYGMEPE; -.
DR OrthoDB; EOG7S7SFK; -.
DR PhylomeDB; P15374; -.
DR SABIO-RK; P15374; -.
DR ChiTaRS; UCHL3; human.
DR EvolutionaryTrace; P15374; -.
DR GeneWiki; UCHL3; -.
DR GenomeRNAi; 7347; -.
DR NextBio; 28762; -.
DR PRO; PR:P15374; -.
DR ArrayExpress; P15374; -.
DR Bgee; P15374; -.
DR CleanEx; HS_UCHL3; -.
DR Genevestigator; P15374; -.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0004221; F:ubiquitin thiolesterase activity; TAS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; NAS:UniProtKB.
DR Gene3D; 3.40.532.10; -; 1.
DR InterPro; IPR001578; Peptidase_C12.
DR PANTHER; PTHR10589; PTHR10589; 1.
DR Pfam; PF01088; Peptidase_C12; 1.
DR PRINTS; PR00707; UBCTHYDRLASE.
DR PROSITE; PS00140; UCH_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytoplasm; Hydrolase; Phosphoprotein;
KW Protease; Reference proteome; Thiol protease; Ubl conjugation pathway.
FT CHAIN 1 230 Ubiquitin carboxyl-terminal hydrolase
FT isozyme L3.
FT /FTId=PRO_0000211061.
FT REGION 8 13 Interaction with ubiquitin.
FT REGION 152 159 Interaction with ubiquitin.
FT REGION 219 224 Interaction with ubiquitin.
FT ACT_SITE 95 95 Nucleophile.
FT ACT_SITE 169 169 Proton donor (Probable).
FT SITE 184 184 Important for enzyme activity (By
FT similarity).
FT MOD_RES 130 130 Phosphoserine.
FT MUTAGEN 33 33 D->A: Decreased interaction with
FT diubiquitin. No accumulation of free
FT diubiquitin. Decreased levels of
FT polyubiquitinated lysozyme.
FT MUTAGEN 95 95 C->A: Increased interaction with
FT diubiquitin.
FT MUTAGEN 95 95 C->S: Abolishes enzymatic activity.
FT Increased interaction with diubiquitin.
FT HELIX 13 22
FT STRAND 29 33
FT HELIX 39 42
FT STRAND 49 57
FT HELIX 60 76
FT HELIX 92 94
FT HELIX 95 105
FT HELIX 106 110
FT HELIX 118 126
FT HELIX 131 139
FT HELIX 142 152
FT STRAND 155 157
FT STRAND 168 176
FT STRAND 179 183
FT STRAND 187 189
FT STRAND 191 195
FT TURN 198 200
FT HELIX 201 215
FT STRAND 223 229
SQ SEQUENCE 230 AA; 26183 MW; 8ACACE6E1D86FD55 CRC64;
MEGQRWLPLE ANPEVTNQFL KQLGLHPNWQ FVDVYGMDPE LLSMVPRPVC AVLLLFPITE
KYEVFRTEEE EKIKSQGQDV TSSVYFMKQT ISNACGTIGL IHAIANNKDK MHFESGSTLK
KFLEESVSMS PEERARYLEN YDAIRVTHET SAHEGQTEAP SIDEKVDLHF IALVHVDGHL
YELDGRKPFP INHGETSDET LLEDAIEVCK KFMERDPDEL RFNAIALSAA
//
ID UCHL3_HUMAN Reviewed; 230 AA.
AC P15374; B2R970; Q5TBK8; Q6IBE9;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L3;
DE Short=UCH-L3;
DE EC=3.4.19.12;
DE AltName: Full=Ubiquitin thioesterase L3;
GN Name=UCHL3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=2530630; DOI=10.1126/science.2530630;
RA Wilkinson K.D., Lee K., Deshpande S., Duerksen-Hughes P., Boss J.M.,
RA Pohl J.;
RT "The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal
RT hydrolase.";
RL Science 246:670-673(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, ENZYME ACTIVITY, TISSUE SPECIFICITY, AND MUTAGENESIS OF
RP CYS-95.
RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532;
RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.;
RT "Cleavage of the C-terminus of NEDD8 by UCH-L3.";
RL Biochem. Biophys. Res. Commun. 251:688-692(1998).
RN [9]
RP IDENTIFICATION AS TUMOR-ASSOCIATED ANTIGEN BY MASS SPECTROMETRY.
RX PubMed=14595809; DOI=10.1002/pmic.200300594;
RA Nam M.J., Madoz-Gurpide J., Wang H., Lescure P., Schmalbach C.E.,
RA Zhao R., Misek D.E., Kuick R., Brenner D.E., Hanash S.M.;
RT "Molecular profiling of the immune response in colon cancer using
RT protein microarrays: occurrence of autoantibodies to ubiquitin C-
RT terminal hydrolase L3.";
RL Proteomics 3:2108-2115(2003).
RN [10]
RP SUBSTRATE SPECIFICITY.
RX PubMed=15157086; DOI=10.1021/bi049722j;
RA Mason D.E., Ek J., Peters E.C., Harris J.L.;
RT "Substrate profiling of deubiquitin hydrolases with a positional
RT scanning library and mass spectrometry.";
RL Biochemistry 43:6535-6544(2004).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-130, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH UBIQUITIN,
RP FUNCTION, ENZYME REGULATION, AND MUTAGENESIS OF ASP-33 AND CYS-95.
RX PubMed=19154770; DOI=10.1016/j.neuint.2008.12.013;
RA Setsuie R., Sakurai M., Sakaguchi Y., Wada K.;
RT "Ubiquitin dimers control the hydrolase activity of UCH-L3.";
RL Neurochem. Int. 54:314-321(2009).
RN [14]
RP ENZYME ACTIVITY, AND MUTAGENESIS OF ASP-33 AND CYS-95.
RX PubMed=20380862; DOI=10.1016/j.neuint.2010.03.021;
RA Setsuie R., Suzuki M., Tsuchiya Y., Wada K.;
RT "Skeletal muscles of Uchl3 knockout mice show polyubiquitinated
RT protein accumulation and stress responses.";
RL Neurochem. Int. 56:911-918(2010).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP FUNCTION.
RX PubMed=21762696; DOI=10.1016/j.febslet.2011.06.037;
RA Dennissen F.J., Kholod N., Hermes D.J., Kemmerling N.,
RA Steinbusch H.W., Dantuma N.P., van Leeuwen F.W.;
RT "Mutant ubiquitin (UBB(+1)) associated with neurodegenerative
RT disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-
RT L3).";
RL FEBS Lett. 585:2568-2574(2011).
RN [17]
RP FUNCTION, AND LINKAGE SPECIFICITY.
RX PubMed=22689415; DOI=10.1002/cbic.201200261;
RA Iphofer A., Kummer A., Nimtz M., Ritter A., Arnold T., Frank R.,
RA van den Heuvel J., Kessler B.M., Jansch L., Franke R.;
RT "Profiling ubiquitin linkage specificities of deubiquitinating enzymes
RT with branched ubiquitin isopeptide probes.";
RL ChemBioChem 13:1416-1420(2012).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=9233788; DOI=10.1093/emboj/16.13.3787;
RA Johnston S.C., Larsen C.N., Cook W.J., Wilkinson K.D., Hill C.P.;
RT "Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8-
RT A resolution.";
RL EMBO J. 16:3787-3796(1997).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) IN COMPLEX WITH UBIQUITIN
RP VINYLMETHYLESTER, AND ENZYME ACTIVITY.
RX PubMed=15531586; DOI=10.1074/jbc.M410770200;
RA Misaghi S., Galardy P.J., Meester W.J.N., Ovaa H., Ploegh H.L.,
RA Gaudet R.;
RT "Structure of the ubiquitin hydrolase UCH-L3 complexed with a suicide
RT substrate.";
RL J. Biol. Chem. 280:1512-1520(2005).
CC -!- FUNCTION: Deubiquitinating enzyme (DUB) that controls levels of
CC cellular ubiquitin through processing of ubiquitin precursors and
CC ubiquitinated proteins. Thiol protease that recognizes and
CC hydrolyzes a peptide bond at the C-terminal glycine of either
CC ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at
CC position P3", and exhibits a preference towards 'Lys-48'-linked
CC Ubiquitin chains. Deubiquitinates ENAC in apical compartments,
CC thereby regulating apical membrane recycling. Indirectly increases
CC the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-
CC signaling and insulin-induced adipogenesis. Required for stress-
CC response retinal, skeletal muscle and germ cell maintenance. May
CC be involved in working memory. Can hydrolyze UBB(+1), a mutated
CC form of ubiquitin which is not effectively degraded by the
CC proteasome and is associated with neurogenerative disorders.
CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester,
CC thioester, amide, peptide and isopeptide bonds formed by the C-
CC terminal Gly of ubiquitin (a 76-residue protein attached to
CC proteins as an intracellular targeting signal).
CC -!- ENZYME REGULATION: Inhibited by monoubiquitin and diubiquitin.
CC -!- SUBUNIT: Preferentially binds diubiquitin; the interaction does
CC not hydrolyze diubiquitin but, in vitro, inhibits the hydrolyzing
CC activity on other substrates.
CC -!- INTERACTION:
CC Q15797:SMAD1; NbExp=2; IntAct=EBI-954554, EBI-1567153;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Highly expressed in heart, skeletal muscle,
CC and testis.
CC -!- MISCELLANEOUS: Identified as a tumor-specific antigen in colon
CC cancer.
CC -!- SIMILARITY: Belongs to the peptidase C12 family.
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DR EMBL; M30496; AAA36791.1; -; mRNA.
DR EMBL; BT019359; AAV38166.1; -; mRNA.
DR EMBL; CR456855; CAG33136.1; -; mRNA.
DR EMBL; AK313665; BAG36417.1; -; mRNA.
DR EMBL; AL137244; CAI12419.1; -; Genomic_DNA.
DR EMBL; CH471093; EAW80542.1; -; Genomic_DNA.
DR EMBL; BC018125; AAH18125.1; -; mRNA.
DR PIR; A40085; A40085.
DR RefSeq; NP_001257881.1; NM_001270952.1.
DR RefSeq; NP_005993.1; NM_006002.4.
DR UniGene; Hs.162241; -.
DR PDB; 1UCH; X-ray; 1.80 A; A=1-230.
DR PDB; 1XD3; X-ray; 1.45 A; A/C=1-230.
DR PDBsum; 1UCH; -.
DR PDBsum; 1XD3; -.
DR ProteinModelPortal; P15374; -.
DR SMR; P15374; 2-230.
DR DIP; DIP-29135N; -.
DR IntAct; P15374; 10.
DR MINT; MINT-2863935; -.
DR STRING; 9606.ENSP00000366819; -.
DR BindingDB; P15374; -.
DR ChEMBL; CHEMBL6195; -.
DR MEROPS; C12.003; -.
DR PhosphoSite; P15374; -.
DR DMDM; 136682; -.
DR OGP; P15374; -.
DR REPRODUCTION-2DPAGE; IPI00011250; -.
DR PaxDb; P15374; -.
DR PeptideAtlas; P15374; -.
DR PRIDE; P15374; -.
DR DNASU; 7347; -.
DR Ensembl; ENST00000377595; ENSP00000366819; ENSG00000118939.
DR GeneID; 7347; -.
DR KEGG; hsa:7347; -.
DR UCSC; uc001vjq.4; human.
DR CTD; 7347; -.
DR GeneCards; GC13P076123; -.
DR HGNC; HGNC:12515; UCHL3.
DR HPA; HPA019678; -.
DR MIM; 603090; gene.
DR neXtProt; NX_P15374; -.
DR PharmGKB; PA37162; -.
DR eggNOG; NOG327708; -.
DR HOGENOM; HOG000182400; -.
DR HOVERGEN; HBG075483; -.
DR KO; K05609; -.
DR OMA; VYGMEPE; -.
DR OrthoDB; EOG7S7SFK; -.
DR PhylomeDB; P15374; -.
DR SABIO-RK; P15374; -.
DR ChiTaRS; UCHL3; human.
DR EvolutionaryTrace; P15374; -.
DR GeneWiki; UCHL3; -.
DR GenomeRNAi; 7347; -.
DR NextBio; 28762; -.
DR PRO; PR:P15374; -.
DR ArrayExpress; P15374; -.
DR Bgee; P15374; -.
DR CleanEx; HS_UCHL3; -.
DR Genevestigator; P15374; -.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0004221; F:ubiquitin thiolesterase activity; TAS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; NAS:UniProtKB.
DR Gene3D; 3.40.532.10; -; 1.
DR InterPro; IPR001578; Peptidase_C12.
DR PANTHER; PTHR10589; PTHR10589; 1.
DR Pfam; PF01088; Peptidase_C12; 1.
DR PRINTS; PR00707; UBCTHYDRLASE.
DR PROSITE; PS00140; UCH_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytoplasm; Hydrolase; Phosphoprotein;
KW Protease; Reference proteome; Thiol protease; Ubl conjugation pathway.
FT CHAIN 1 230 Ubiquitin carboxyl-terminal hydrolase
FT isozyme L3.
FT /FTId=PRO_0000211061.
FT REGION 8 13 Interaction with ubiquitin.
FT REGION 152 159 Interaction with ubiquitin.
FT REGION 219 224 Interaction with ubiquitin.
FT ACT_SITE 95 95 Nucleophile.
FT ACT_SITE 169 169 Proton donor (Probable).
FT SITE 184 184 Important for enzyme activity (By
FT similarity).
FT MOD_RES 130 130 Phosphoserine.
FT MUTAGEN 33 33 D->A: Decreased interaction with
FT diubiquitin. No accumulation of free
FT diubiquitin. Decreased levels of
FT polyubiquitinated lysozyme.
FT MUTAGEN 95 95 C->A: Increased interaction with
FT diubiquitin.
FT MUTAGEN 95 95 C->S: Abolishes enzymatic activity.
FT Increased interaction with diubiquitin.
FT HELIX 13 22
FT STRAND 29 33
FT HELIX 39 42
FT STRAND 49 57
FT HELIX 60 76
FT HELIX 92 94
FT HELIX 95 105
FT HELIX 106 110
FT HELIX 118 126
FT HELIX 131 139
FT HELIX 142 152
FT STRAND 155 157
FT STRAND 168 176
FT STRAND 179 183
FT STRAND 187 189
FT STRAND 191 195
FT TURN 198 200
FT HELIX 201 215
FT STRAND 223 229
SQ SEQUENCE 230 AA; 26183 MW; 8ACACE6E1D86FD55 CRC64;
MEGQRWLPLE ANPEVTNQFL KQLGLHPNWQ FVDVYGMDPE LLSMVPRPVC AVLLLFPITE
KYEVFRTEEE EKIKSQGQDV TSSVYFMKQT ISNACGTIGL IHAIANNKDK MHFESGSTLK
KFLEESVSMS PEERARYLEN YDAIRVTHET SAHEGQTEAP SIDEKVDLHF IALVHVDGHL
YELDGRKPFP INHGETSDET LLEDAIEVCK KFMERDPDEL RFNAIALSAA
//
MIM
603090
*RECORD*
*FIELD* NO
603090
*FIELD* TI
*603090 UBIQUITIN CARBOXYL-TERMINAL ESTERASE L3; UCHL3
*FIELD* TX
CLONING
Covalent attachment of the C terminus of ubiquitin (191339) to cellular
read moreproteins plays a role in a variety of cellular processes. Ubiquitin
C-terminal hydrolysis is catalyzed by deubiquitinating (DUB) enzymes and
is necessary for several functions, including liberation of monomeric
ubiquitin from the precursors encoded by ubiquitin genes and recycling
of ubiquitin monomers. There are 2 distinct families of DUBs,
ubiquitin-specific proteases (UBPs) and ubiquitin C-terminal hydrolases
(UCHs). Mayer and Wilkinson (1989) identified 4 distinct UCH activities
from bovine thymus. All 4 were thiol proteases and had high-affinity
binding sites for ubiquitin. Wilkinson et al. (1989) purified the
predominant isozyme, UCHL3, and raised antibodies against it. By
screening a human B-cell expression library with the antibodies, the
authors isolated cDNAs encoding human UCHL3. The predicted 230-amino
acid human UCHL3 protein is 54% identical to UCHL1 (191342).
Using Northern blot analysis, Kurihara et al. (2002) found that mouse
Uchl3 was expressed at all embryonic stages examined, beginning at
embryonic day 7. In adult tissues, Uchl3 was variably expressed in all
tissues examined, with highest expression in testis.
GENE FUNCTION
Wilkinson et al. (1989) showed that recombinant UCHL3 protein displayed
UCH activity in vitro.
BIOCHEMICAL FEATURES
Johnston et al. (1997) determined the crystal structure of human UCHL3.
GENE STRUCTURE
Kurihara et al. (2002) determined that the 5-prime ends of the mouse and
human UCHL3 genes contain a conserved CpG island.
MAPPING
By genomic sequence analysis, Kurihara et al. (2002) mapped the UCHL3
gene to a region of human chromosome 13q22. The mouse Uchl3 gene maps to
a syntenic region on chromosome 14.
ANIMAL MODEL
Altered function of the ubiquitin pathway has been implicated in the
etiology of neurodegeneration. For example, Saigoh et al. (1999) showed
that gracile axonal dystrophy (gad) mutant mice, which harbor a deletion
within the gene encoding ubiquitin C-terminal hydrolase L1 (UCHL1;
191342), display sensory ataxia followed by posterior paralysis and
lethality. However, mice homozygous for a targeted deletion of the
related Uchl3 gene are indistinguishable from wildtype (Kurihara et al.,
2000). To assess whether the 2 hydrolases have redundant function,
Kurihara et al. (2001) generated mice homozygous for both Uchl1(gad) and
Uchl3(delta3-7). The double homozygotes weighed 30% less than single
homozygotes and displayed an earlier onset of lethality, possibly due to
dysphagia. Axonal degeneration of the nucleus tractus solitarius and
area postrema of the medulla was noted in these mice. The double
homozygotes also displayed a more severe axonal degeneration of the
gracile tract of the medulla and spinal cord than had been observed in
Uchl1(gad) single homozygotes. In addition, degeneration of dorsal root
ganglia cell bodies was detected in both the double homozygotes and
Uchl3(delta3-7) single homozygotes. Given that both Uchl1(gad) and
Uchl3(delta3-7) single homozygotes displayed distinct degenerative
defects that were exacerbated in the double homozygotes, the authors
concluded that Uchl1 and Uchl3 may have both separate and overlapping
functions in the maintenance of neurons of the gracile tract, nucleus
tractus solitarius, and area postrema.
The Acrg minimal region is a 1.5- to 1.7-Mb domain defined by genetic
complementation among deletions generated around the endothelin B
receptor (EDNRB; 131244) on chromosome 14 in mice. The region contains
both Uchl3 and an F-box/PDZ/LIM domain protein, Lmo7 (604362). To
dissect the Acrg minimal region further, Semenova et al. (2003) utilized
Cre-loxP-mediated chromosome engineering to generate a targeted 800-kb
deletion, Lmo7(delta800), that removed the distal portion of the region.
The deletion included Uchl3, Lmo7, and an additional 500 kb downstream
of Lmo7. Forty percent of mice homozygous for this deletion died between
birth and weaning, and were severely runted. Both Uchl3(delta3-7) and
Lmo7(delta800) mutants displayed retinal, muscular, and growth
retardation, but the severity of the muscular degeneration and growth
retardation were enhanced in Lmo7(delta800) homozygotes. The authors
suggested that the increase in severity may reflect an interaction
between Uchl3 and Lmo7 in the ubiquitin-mediated protein degradation
pathway.
*FIELD* RF
1. Johnston, S. C.; Larsen, C. N.; Cook, W. J.; Wilkinson, K. D.;
Hill, C. P.: Crystal structure of a deubiquitinating enzyme (human
UCH-L3) at 1.8 angstrom resolution. EMBO J. 16: 3787-3796, 1997.
2. Kurihara, L. J.; Kikuchi, T.; Wada, K.; Tilghman, S. M.: Loss
of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis
and dysphagia. Hum. Molec. Genet. 10: 1963-1970, 2001.
3. Kurihara, L. J.; Semenova, E.; Levorse, J. M.; Tilghman, S. M.
: Expression and functional analysis of Uch-L3 during mouse development. Molec.
Cell. Biol. 20: 2498-2504, 2000.
4. Kurihara, L. J.; Semenova, E.; Miller, W.; Ingram, R. S.; Guan,
X.-J.; Tilghman, S. M.: Candidate genes required for embryonic development:
a comparative analysis of distal mouse chromosome 14 and human chromosome
13q22. Genomics 79: 154-161, 2002.
5. Mayer, A. N.; Wilkinson, K. D.: Detection, resolution, and nomenclature
of multiple ubiquitin carboxyl-terminal esterases from bovine calf
thymus. Biochemistry 28: 166-172, 1989.
6. Saigoh, K.; Wang, Y.-L.; Suh, J.-G.; Yamanishi, T.; Sakai, Y.;
Kiyosawa, H.; Harada, T.; Ichihara, N.; Wakana, S.; Kikuchi, T.; Wada,
K.: Intragenic deletion in the gene encoding ubiquitin carboxy-terminal
hydrolase in gad mice. Nature Genet. 23: 47-51, 1999.
7. Semenova, E.; Wang, X.; Jablonski, M. M.; Levorse, J.; Tilghman,
S. M.: An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse
chromosome 14 causes defects in viability, postnatal growth and degeneration
of muscle and retina. Hum. Molec. Genet. 12: 1301-1312, 2003.
8. Wilkinson, K. D.; Lee, K.; Deshpande, S.; Duerksen-Hughes, P.;
Boss, J. M.; Pohl, J.: The neuron-specific protein PGP 9.5 is a ubiquitin
carboxyl-terminal hydrolase. Science 246: 670-673, 1989.
*FIELD* CN
Patricia A. Hartz - updated: 2/25/2009
George E. Tiller - updated: 3/10/2005
George E. Tiller - updated: 1/31/2002
*FIELD* CD
Rebekah S. Rasooly: 10/5/1998
*FIELD* ED
mgross: 02/27/2009
terry: 2/25/2009
alopez: 3/10/2005
carol: 5/12/2004
terry: 3/8/2002
cwells: 2/6/2002
cwells: 1/31/2002
alopez: 10/5/1998
*RECORD*
*FIELD* NO
603090
*FIELD* TI
*603090 UBIQUITIN CARBOXYL-TERMINAL ESTERASE L3; UCHL3
*FIELD* TX
CLONING
Covalent attachment of the C terminus of ubiquitin (191339) to cellular
read moreproteins plays a role in a variety of cellular processes. Ubiquitin
C-terminal hydrolysis is catalyzed by deubiquitinating (DUB) enzymes and
is necessary for several functions, including liberation of monomeric
ubiquitin from the precursors encoded by ubiquitin genes and recycling
of ubiquitin monomers. There are 2 distinct families of DUBs,
ubiquitin-specific proteases (UBPs) and ubiquitin C-terminal hydrolases
(UCHs). Mayer and Wilkinson (1989) identified 4 distinct UCH activities
from bovine thymus. All 4 were thiol proteases and had high-affinity
binding sites for ubiquitin. Wilkinson et al. (1989) purified the
predominant isozyme, UCHL3, and raised antibodies against it. By
screening a human B-cell expression library with the antibodies, the
authors isolated cDNAs encoding human UCHL3. The predicted 230-amino
acid human UCHL3 protein is 54% identical to UCHL1 (191342).
Using Northern blot analysis, Kurihara et al. (2002) found that mouse
Uchl3 was expressed at all embryonic stages examined, beginning at
embryonic day 7. In adult tissues, Uchl3 was variably expressed in all
tissues examined, with highest expression in testis.
GENE FUNCTION
Wilkinson et al. (1989) showed that recombinant UCHL3 protein displayed
UCH activity in vitro.
BIOCHEMICAL FEATURES
Johnston et al. (1997) determined the crystal structure of human UCHL3.
GENE STRUCTURE
Kurihara et al. (2002) determined that the 5-prime ends of the mouse and
human UCHL3 genes contain a conserved CpG island.
MAPPING
By genomic sequence analysis, Kurihara et al. (2002) mapped the UCHL3
gene to a region of human chromosome 13q22. The mouse Uchl3 gene maps to
a syntenic region on chromosome 14.
ANIMAL MODEL
Altered function of the ubiquitin pathway has been implicated in the
etiology of neurodegeneration. For example, Saigoh et al. (1999) showed
that gracile axonal dystrophy (gad) mutant mice, which harbor a deletion
within the gene encoding ubiquitin C-terminal hydrolase L1 (UCHL1;
191342), display sensory ataxia followed by posterior paralysis and
lethality. However, mice homozygous for a targeted deletion of the
related Uchl3 gene are indistinguishable from wildtype (Kurihara et al.,
2000). To assess whether the 2 hydrolases have redundant function,
Kurihara et al. (2001) generated mice homozygous for both Uchl1(gad) and
Uchl3(delta3-7). The double homozygotes weighed 30% less than single
homozygotes and displayed an earlier onset of lethality, possibly due to
dysphagia. Axonal degeneration of the nucleus tractus solitarius and
area postrema of the medulla was noted in these mice. The double
homozygotes also displayed a more severe axonal degeneration of the
gracile tract of the medulla and spinal cord than had been observed in
Uchl1(gad) single homozygotes. In addition, degeneration of dorsal root
ganglia cell bodies was detected in both the double homozygotes and
Uchl3(delta3-7) single homozygotes. Given that both Uchl1(gad) and
Uchl3(delta3-7) single homozygotes displayed distinct degenerative
defects that were exacerbated in the double homozygotes, the authors
concluded that Uchl1 and Uchl3 may have both separate and overlapping
functions in the maintenance of neurons of the gracile tract, nucleus
tractus solitarius, and area postrema.
The Acrg minimal region is a 1.5- to 1.7-Mb domain defined by genetic
complementation among deletions generated around the endothelin B
receptor (EDNRB; 131244) on chromosome 14 in mice. The region contains
both Uchl3 and an F-box/PDZ/LIM domain protein, Lmo7 (604362). To
dissect the Acrg minimal region further, Semenova et al. (2003) utilized
Cre-loxP-mediated chromosome engineering to generate a targeted 800-kb
deletion, Lmo7(delta800), that removed the distal portion of the region.
The deletion included Uchl3, Lmo7, and an additional 500 kb downstream
of Lmo7. Forty percent of mice homozygous for this deletion died between
birth and weaning, and were severely runted. Both Uchl3(delta3-7) and
Lmo7(delta800) mutants displayed retinal, muscular, and growth
retardation, but the severity of the muscular degeneration and growth
retardation were enhanced in Lmo7(delta800) homozygotes. The authors
suggested that the increase in severity may reflect an interaction
between Uchl3 and Lmo7 in the ubiquitin-mediated protein degradation
pathway.
*FIELD* RF
1. Johnston, S. C.; Larsen, C. N.; Cook, W. J.; Wilkinson, K. D.;
Hill, C. P.: Crystal structure of a deubiquitinating enzyme (human
UCH-L3) at 1.8 angstrom resolution. EMBO J. 16: 3787-3796, 1997.
2. Kurihara, L. J.; Kikuchi, T.; Wada, K.; Tilghman, S. M.: Loss
of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis
and dysphagia. Hum. Molec. Genet. 10: 1963-1970, 2001.
3. Kurihara, L. J.; Semenova, E.; Levorse, J. M.; Tilghman, S. M.
: Expression and functional analysis of Uch-L3 during mouse development. Molec.
Cell. Biol. 20: 2498-2504, 2000.
4. Kurihara, L. J.; Semenova, E.; Miller, W.; Ingram, R. S.; Guan,
X.-J.; Tilghman, S. M.: Candidate genes required for embryonic development:
a comparative analysis of distal mouse chromosome 14 and human chromosome
13q22. Genomics 79: 154-161, 2002.
5. Mayer, A. N.; Wilkinson, K. D.: Detection, resolution, and nomenclature
of multiple ubiquitin carboxyl-terminal esterases from bovine calf
thymus. Biochemistry 28: 166-172, 1989.
6. Saigoh, K.; Wang, Y.-L.; Suh, J.-G.; Yamanishi, T.; Sakai, Y.;
Kiyosawa, H.; Harada, T.; Ichihara, N.; Wakana, S.; Kikuchi, T.; Wada,
K.: Intragenic deletion in the gene encoding ubiquitin carboxy-terminal
hydrolase in gad mice. Nature Genet. 23: 47-51, 1999.
7. Semenova, E.; Wang, X.; Jablonski, M. M.; Levorse, J.; Tilghman,
S. M.: An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse
chromosome 14 causes defects in viability, postnatal growth and degeneration
of muscle and retina. Hum. Molec. Genet. 12: 1301-1312, 2003.
8. Wilkinson, K. D.; Lee, K.; Deshpande, S.; Duerksen-Hughes, P.;
Boss, J. M.; Pohl, J.: The neuron-specific protein PGP 9.5 is a ubiquitin
carboxyl-terminal hydrolase. Science 246: 670-673, 1989.
*FIELD* CN
Patricia A. Hartz - updated: 2/25/2009
George E. Tiller - updated: 3/10/2005
George E. Tiller - updated: 1/31/2002
*FIELD* CD
Rebekah S. Rasooly: 10/5/1998
*FIELD* ED
mgross: 02/27/2009
terry: 2/25/2009
alopez: 3/10/2005
carol: 5/12/2004
terry: 3/8/2002
cwells: 2/6/2002
cwells: 1/31/2002
alopez: 10/5/1998