P15374 (UCHL3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ubiquitin carboxyl-terminal hydrolase isozyme L3
Short name=UCH-L3
EC=3.4.19.12

Alternative name(s):
Ubiquitin thioesterase L3

Gene names

Name:

UCHL3

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	230 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins. Thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at position P3", and exhibits a preference towards 'Lys-48'-linked Ubiquitin chains. Deubiquitinates ENAC in apical compartments, thereby regulating apical membrane recycling. Indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. Required for stress-response retinal, skeletal muscle and germ cell maintenance. May be involved in working memory. Can hydrolyze UBB(+1), a mutated form of ubiquitin which is not effectively degraded by the proteasome and is associated with neurogenerative disorders. Ref.1 Ref.8 Ref.13 Ref.16 Ref.17
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.8 Ref.14 Ref.19
Enzyme regulation	Inhibited by monoubiquitin and diubiquitin. Ref.13
Subunit structure	Preferentially binds diubiquitin; the interaction does not hydrolyze diubiquitin but, in vitro, inhibits the hydrolyzing activity on other substrates.
Subcellular location	Cytoplasm.
Tissue specificity	Highly expressed in heart, skeletal muscle, and testis. Ref.8
Miscellaneous	Identified as a tumor-specific antigen in colon cancer.
Sequence similarities	Belongs to the peptidase C12 family.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ubiquitin-dependent protein catabolic process Non-traceable author statement. Source: UniProtKB
Cellular_component	mitochondrion Inferred from direct assay. Source: HPA nucleus Inferred from direct assay. Source: HPA
Molecular_function	cysteine-type peptidase activity Inferred from electronic annotation. Source: UniProtKB-KW peptidase activity Inferred from direct assay Ref.16. Source: UniProtKB ubiquitin binding Inferred from direct assay Ref.13. Source: UniProtKB ubiquitin thiolesterase activity Traceable author statement Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 230

230

Ubiquitin carboxyl-terminal hydrolase isozyme L3

PRO_0000211061

Regions

Region

8 – 13

6

Interaction with ubiquitin

Region

152 – 159

8

Interaction with ubiquitin

Region

219 – 224

6

Interaction with ubiquitin

Sites

Active site

95

1

Nucleophile

Active site

169

1

Proton donor Probable

Site

184

1

Important for enzyme activity By similarity

Amino acid modifications

Modified residue

130

1

Phosphoserine Ref.12

Experimental info

Mutagenesis

33

1

D → A: Decreased interaction with diubiquitin. No accumulation of free diubiquitin. Decreased levels of polyubiquitinated lysozyme. Ref.13 Ref.14

Mutagenesis

95

1

C → A: Increased interaction with diubiquitin. Ref.8 Ref.13 Ref.14

Mutagenesis

95

1

C → S: Abolishes enzymatic activity. Increased interaction with diubiquitin. Ref.8 Ref.13 Ref.14

Secondary structure

1

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230

Helix Strand Turn

Details...

Helix

13 – 22

10

Beta strand

29 – 33

5

Helix

39 – 42

4

Beta strand

49 – 57

9

Helix

60 – 76

17

Helix

92 – 94

3

Helix

95 – 105

11

Helix

106 – 110

5

Helix

118 – 126

9

Helix

131 – 139

9

Helix

142 – 152

11

Beta strand

155 – 157

3

Beta strand

168 – 176

9

Beta strand

179 – 183

5

Beta strand

187 – 189

3

Beta strand

191 – 195

5

Turn

198 – 200

3

Helix

201 – 215

15

Beta strand

223 – 229

7

Sequences

	Sequence		Length	Mass (Da)
	P15374 [UniParc]. Last modified April 1, 1990. Version 1. Checksum: 8ACACE6E1D86FD55	FASTA	230	26,183
	10 20 30 40 50 60 MEGQRWLPLE ANPEVTNQFL KQLGLHPNWQ FVDVYGMDPE LLSMVPRPVC AVLLLFPITE 70 80 90 100 110 120 KYEVFRTEEE EKIKSQGQDV TSSVYFMKQT ISNACGTIGL IHAIANNKDK MHFESGSTLK 130 140 150 160 170 180 KFLEESVSMS PEERARYLEN YDAIRVTHET SAHEGQTEAP SIDEKVDLHF IALVHVDGHL 190 200 210 220 230 YELDGRKPFP INHGETSDET LLEDAIEVCK KFMERDPDEL RFNAIALSAA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase." Wilkinson K.D., Lee K., Deshpande S., Duerksen-Hughes P., Boss J.M., Pohl J. Science 246:670-673(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	"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. , 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]. Tissue: Brain.
[5]	"The DNA sequence and analysis of human chromosome 13." Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T. Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	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. , 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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]. Tissue: Lung.
[8]	"Cleavage of the C-terminus of NEDD8 by UCH-L3." Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T. Biochem. Biophys. Res. Commun. 251:688-692(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME ACTIVITY, TISSUE SPECIFICITY, MUTAGENESIS OF CYS-95.
[9]	"Molecular profiling of the immune response in colon cancer using protein microarrays: occurrence of autoantibodies to ubiquitin C-terminal hydrolase L3." Nam M.J., Madoz-Gurpide J., Wang H., Lescure P., Schmalbach C.E., Zhao R., Misek D.E., Kuick R., Brenner D.E., Hanash S.M. Proteomics 3:2108-2115(2003) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION AS TUMOR-ASSOCIATED ANTIGEN BY MASS SPECTROMETRY.
[10]	"Substrate profiling of deubiquitin hydrolases with a positional scanning library and mass spectrometry." Mason D.E., Ek J., Peters E.C., Harris J.L. Biochemistry 43:6535-6544(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBSTRATE SPECIFICITY.
[11]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Embryonic kidney.
[12]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-130, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"Ubiquitin dimers control the hydrolase activity of UCH-L3." Setsuie R., Sakurai M., Sakaguchi Y., Wada K. Neurochem. Int. 54:314-321(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH UBIQUITIN, FUNCTION, ENZYME REGULATION, MUTAGENESIS OF ASP-33 AND CYS-95.
[14]	"Skeletal muscles of Uchl3 knockout mice show polyubiquitinated protein accumulation and stress responses." Setsuie R., Suzuki M., Tsuchiya Y., Wada K. Neurochem. Int. 56:911-918(2010) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME ACTIVITY, MUTAGENESIS OF ASP-33 AND CYS-95.
[15]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[16]	"Mutant ubiquitin (UBB(+1)) associated with neurodegenerative disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3)." Dennissen F.J., Kholod N., Hermes D.J., Kemmerling N., Steinbusch H.W., Dantuma N.P., van Leeuwen F.W. FEBS Lett. 585:2568-2574(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[17]	"Profiling ubiquitin linkage specificities of deubiquitinating enzymes with branched ubiquitin isopeptide probes." Iphofer A., Kummer A., Nimtz M., Ritter A., Arnold T., Frank R., van den Heuvel J., Kessler B.M., Jansch L., Franke R. ChemBioChem 13:1416-1420(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, LINKAGE SPECIFICITY.
[18]	"Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8-A resolution." Johnston S.C., Larsen C.N., Cook W.J., Wilkinson K.D., Hill C.P. EMBO J. 16:3787-3796(1997) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
[19]	"Structure of the ubiquitin hydrolase UCH-L3 complexed with a suicide substrate." Misaghi S., Galardy P.J., Meester W.J.N., Ovaa H., Ploegh H.L., Gaudet R. J. Biol. Chem. 280:1512-1520(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) IN COMPLEX WITH UBIQUITIN VINYLMETHYLESTER, ENZYME ACTIVITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M30496 mRNA. Translation: AAA36791.1.
BT019359 mRNA. Translation: AAV38166.1.
CR456855 mRNA. Translation: CAG33136.1.
AK313665 mRNA. Translation: BAG36417.1.
AL137244 Genomic DNA. Translation: CAI12419.1.
CH471093 Genomic DNA. Translation: EAW80542.1.
BC018125 mRNA. Translation: AAH18125.1.

IPI

IPI00011250.

PIR

A40085.

RefSeq

NP_001257881.1. NM_001270952.1.
NP_005993.1. NM_006002.4.

UniGene

Hs.162241.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1UCH	X-ray	1.80	A	1-230	[»]
1XD3	X-ray	1.45	A/C	1-230	[»]

ProteinModelPortal

P15374.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29135N.

IntAct

P15374. 6 interactions.

MINT

MINT-2863935.

STRING

9606.ENSP00000366819.

Protein family/group databases

MEROPS

C12.003.

PTM databases

PhosphoSite

P15374.

Polymorphism databases

DMDM

136682.

2D gel databases

OGP

P15374.

REPRODUCTION-2DPAGE

IPI00011250.

Proteomic databases

PaxDb

P15374.

PeptideAtlas

P15374.

PRIDE

P15374.

Protocols and materials databases

DNASU

7347.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000377595; ENSP00000366819; ENSG00000118939.

GeneID

7347.

KEGG

hsa:7347.

UCSC

uc001vjq.3. human.

Organism-specific databases

CTD

7347.

GeneCards

GC13P076123.

HGNC

HGNC:12515. UCHL3.

HPA

HPA019678.

MIM

603090. gene.

neXtProt

NX_P15374.

PharmGKB

PA37162.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG327708.

HOGENOM

HOG000182400.

HOVERGEN

HBG075483.

KO

K05609.

OMA

QTEAPNI.

OrthoDB

EOG4HX51V.

PhylomeDB

P15374.

Gene expression databases

ArrayExpress

P15374.

Bgee

P15374.

CleanEx

HS_UCHL3.

Genevestigator

P15374.

GermOnline

ENSG00000118939. Homo sapiens.

Family and domain databases

Gene3D

3.40.532.10. 1 hit.

InterPro

IPR001578. Peptidase_C12.
[Graphical view]

PANTHER

PTHR10589. PTHR10589. 1 hit.

Pfam

PF01088. Peptidase_C12. 1 hit.
[Graphical view]

PRINTS

PR00707. UBCTHYDRLASE.

PROSITE

PS00140. UCH_1. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P15374.

ChEMBL

CHEMBL6195.

ChiTaRS

UCHL3. human.

EvolutionaryTrace

P15374.

GenomeRNAi

7347.

NextBio

28762.

SOURCE

Search...

Entry information

Entry name

UCHL3_HUMAN

Accession

Primary (citable) accession number: P15374
Secondary accession number(s): B2R970, Q5TBK8, Q6IBE9

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1990
Last sequence update:	April 1, 1990
Last modified:	May 1, 2013
This is version 133 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.