Reviewed, UniProtKB/Swiss-Prot P09936 (UCHL1_HUMAN)

Names and origin

Protein names

Recommended name:
    Ubiquitin carboxyl-terminal hydrolase isozyme L1
      Short name=UCH-L1
    EC=3.4.19.12
    EC=6.-.-.-
Alternative name(s):
    Ubiquitin thioesterase L1
    Neuron cytoplasmic protein 9.5
    PGP 9.5
      Short name=PGP9.5

Gene names

Name:

UCHL1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	223 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity. Ref.12 Ref.13
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).
Subunit structure	Homodimer. Interacts with SNCA By similarity. Interacts with COPS5.
Subcellular location	Cytoplasm.
Tissue specificity	Found in neuronal cell bodies and processes throughout the neocortex (at protein level). Expressed in neurons and cells of the diffuse neuroendocrine system and their tumors. Weakly expressed in ovary. Ref.12 Ref.5
Post-translational modification	O-glycosylated By similarity.
Involvement in disease	Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic acid have been observed in brains from Alzheimer disease (AD) and Parkinson disease (PD) patients. In AD, UCHL1 was found to be associated with neurofibrillary tangles. Ref.5 Ref.20
Miscellaneous	In contrast to UCHL3, does not hydrolyze a peptide bond at the C-terminal glycine of NEDD8.
Sequence similarities	Belongs to the peptidase C12 family.
Biophysicochemical properties	Kinetic parameters: KM=122 nM for Ub-AMC KM=1.20 µM for ubiquitin ethyl ester Vmax=0.47 µmol/min/mg enzyme toward Ub-AMC Vmax=25 µmol/min/mg enzyme toward ubiquitin ethyl ester

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Molecular function	Hydrolase Ligase Protease Thiol protease
PTM	Glycoprotein Oxidation
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	protein deubiquitination Inferred from direct assay. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular component	nucleus Inferred from direct assay. Source: HPA
Molecular function	cysteine-type endopeptidase activity Ref.11 Inferred from direct assay. Source: UniProtKB ligase activity Inferred from electronic annotation. Source: UniProtKB-KW omega peptidase activity Inferred from direct assay. Source: UniProtKB ubiquitin binding Inferred from direct assay. Source: UniProtKB ubiquitin thiolesterase activity Traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDKN1B	P46527	1	EBI-714860,EBI-519280
COPS5	Q92905	1	EBI-714860,EBI-594661

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 223

223

Ubiquitin carboxyl-terminal hydrolase isozyme L1

PRO_0000211055

Regions

Region

37 – 54

18

Ubiquitin binding 1 Potential

Region

170 – 178

9

Ubiquitin binding 2 Potential

Sites

Active site

90

1

Ref.11

Active site

161

1

Ref.11

Active site

176

1

Ref.11

Site

1

1

Susceptible to oxidation

Site

6

1

Susceptible to oxidation

Site

12

1

Susceptible to oxidation

Site

124

1

Susceptible to oxidation

Site

179

1

Susceptible to oxidation

Site

220

1

Susceptible to oxidation

Natural variations

Natural variant

18

1

S → Y May reduce the risk for PD; loss of dimerization ability and impaired ligase activity. dbSNP rs5030732. Ref.13 Ref.20 Ref.16 Ref.18 Ref.19

VAR_015677

Natural variant

93

1

I → M in a PD patient; impaired enzymatic hydrolase activity. Ref.13 Ref.16 Ref.8 Ref.17

VAR_015678

Experimental info

Mutagenesis

73

1

Q → R: No effect on enzymatic parameters. Ref.11

Mutagenesis

90

1

C → S: Abolishes enzymatic activity. Ref.11 Ref.16

Mutagenesis

97

1

H → Q or N: 2-fold increase in affinity for ubiquitin ethyl ester, slight reduction in enzymatic activity. Ref.11

Mutagenesis

161

1

H → D: 10000-fold decrease in enzymatic activity; no change in affinity for ubiquitin ethyl ester. Ref.11

Mutagenesis

161

1

H → K, Q, N or Y: Abolishes enzymatic activity. Ref.11

Mutagenesis

176

1

D → N: 6-fold decrease in affinity for ubiquitin ethyl ester; 97.5% decrease in enzymatic activity. Ref.11

Secondary structure

1

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223

Helix Strand Turn

Details...

Helix

10 – 19

10

Beta strand

24 – 30

7

Beta strand

39 – 42

4

Beta strand

46 – 54

9

Helix

57 – 70

14

Turn

71 – 74

4

Helix

90 – 100

11

Turn

101 – 105

5

Helix

113 – 120

8

Turn

121 – 123

3

Helix

126 – 135

10

Helix

137 – 147

11

Beta strand

160 – 168

9

Beta strand

171 – 175

5

Beta strand

179 – 181

3

Beta strand

183 – 187

5

Helix

193 – 206

14

Beta strand

215 – 221

7

Sequences

	Sequence		Length	Mass (Da)
	P09936-1 [UniParc]. Last modified November 1, 1990. Version 2. Checksum: C9E972AC4DA5DA8A	FASTA	223	24,824
	10 20 30 40 50 60 MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE 70 80 90 100 110 120 NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE 130 140 150 160 170 180 TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP 190 200 210 220 FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[2]	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].
[3]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung and Muscle.
[4]	"The structure of the human gene encoding protein gene product 9.5 (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase." Day I.N.M., Hinks L.J., Thompson R.J. Biochem. J. 268:521-524(1990) [PubMed: 2163617] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-15.
[5]	"Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases." Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S., Li L. J. Biol. Chem. 279:13256-13264(2004) [PubMed: 14722078] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION, IDENTIFICATION BY MASS SPECTROMETRY, TISSUE SPECIFICITY, DISEASE.
[6]	Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, MASS SPECTROMETRY. Tissue: Brain, Cajal-Retzius cell and Fetal brain cortex.
[7]	"Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel cytoplasmic marker for neurones and neuroendocrine cells." Day I.N.M., Thompson R.J. FEBS Lett. 210:157-160(1987) [PubMed: 2947814] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, PARTIAL PROTEIN SEQUENCE.
[8]	"The ubiquitin pathway in Parkinson's disease." Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C., Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H. Nature 395:451-452(1998) [PubMed: 9774100] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, VARIANT MET-93, BIOPHYSICOCHEMICAL PROPERTIES.
[9]	"Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured human MRC-5 fibroblasts of normal origin and is strongly down-regulated in their SV40 transformed counterparts." Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E. FEBS Lett. 280:235-240(1991) [PubMed: 1849484] [Abstract] Cited for: PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151.
[10]	"Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes." Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E., Vandekerckhove J. Electrophoresis 13:960-969(1992) [PubMed: 1286667] [Abstract] Cited for: PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151.
[11]	"Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active site residues." Larsen C.N., Price J.S., Wilkinson K.D. Biochemistry 35:6735-6744(1996) [PubMed: 8639624] [Abstract] Cited for: ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90; HIS-97; HIS-161 AND ASP-176, BIOPHYSICOCHEMICAL PROPERTIES.
[12]	"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: 9790970] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[13]	"The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility." Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr. Cell 111:209-218(2002) [PubMed: 12408865] [Abstract] Cited for: FUNCTION, CHARACTERIZATION OF VARIANTS TYR-18 AND MET-93.
[14]	"Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)." Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J., Yochem R., Ratovitski E., Sidransky D., Jen J. Oncogene 21:3003-3010(2002) [PubMed: 12082530] [Abstract] Cited for: INTERACTION WITH COPS5.
[15]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[16]	"Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants." Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y., Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K. Biochem. Biophys. Res. Commun. 304:176-183(2003) [PubMed: 12705903] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS TYR-18 AND MET-93, MUTAGENESIS OF CYS-90, BIOPHYSICOCHEMICAL PROPERTIES.
[17]	"The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease." Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G., De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B., Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M. Neurosci. Lett. 270:1-4(1999) [PubMed: 10454131] [Abstract] Cited for: VARIANT MET-93.
[18]	"Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease." Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K., Lynch T., Hardy J., Farrer M. NeuroReport 10:427-429(1999) [PubMed: 10203348] [Abstract] Cited for: VARIANT TYR-18.
[19]	"The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does not confer protection against idiopathic Parkinson's disease." Mellick G.D., Silburn P.A. Neurosci. Lett. 293:127-130(2000) [PubMed: 11027850] [Abstract] Cited for: VARIANT TYR-18.
[20]	"UCHL1 is a Parkinson's disease susceptibility gene." UCHL1 global genetics consortium Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A. Ann. Neurol. 55:512-521(2004) [PubMed: 15048890] [Abstract] Cited for: INVERSE ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON DISEASE.
[21]	Erratum UCHL1 global genetics consortium Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A. Ann. Neurol. 55:899-899(2004)
+	Additional computationally mapped references.

Web resources

GeneReviews

Wikipedia

Ubiquitin carboxy-terminal hydrolase L1 entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

AC095043 Genomic DNA. Translation: AAY40923.1.
CH471069 Genomic DNA. Translation: EAW92983.1.
BC000332 mRNA. Translation: AAH00332.1.
BC005117 mRNA. Translation: AAH05117.1.
BC006305 mRNA. Translation: AAH06305.1.
X17377 Genomic DNA. Translation: CAA35249.1.
X04741 mRNA. Translation: CAA28443.1. Different initiation.
AF076273 , AF060834, AF076269, AF076270, AF076271, AF076272 Genomic DNA. Translation: AAD09172.1.

IPI

IPI00018352.

PIR

A25856.

RefSeq

NP_004172.2.

UniGene

Hs.518731

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2ETL	X-ray	2.40	A/B	1-223	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P09936. 16 interactions.

Protein family/group databases

MEROPS

C12.001.

2-D gel databases

Aarhus/Ghent-2DPAGE

6123. IEF.

DOSAC-COBS-2DPAGE

P09936.

Proteomic databases

PeptideAtlas

P09936.

PRIDE

P09936.

Genome annotation databases

Ensembl

ENSG00000154277. Homo sapiens. [Contig view]

GeneID

7345.

KEGG

hsa:7345.

UCSC

uc003gvo.1. human.

Organism-specific databases

GeneCards

GC04P040953.

H-InvDB

HIX0004176.

HGNC

HGNC:12513. UCHL1.

HPA

CAB002580.
HPA005993.

MIM

191342. gene+phenotype.

Orphanet

2828. Parkinson disease, genetic types.

PharmGKB

PA37160.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P09936.

HOVERGEN

P09936.

OMA

P09936. CRQFTER.

Enzyme and pathway databases

BRENDA

3.1.2.15. 247.
3.4.19.12. 247.

Pathway_Interaction_DB

alphasynuclein_pathway. Alpha-synuclein signaling.

Gene expression databases

ArrayExpress

P09936.

Bgee

P09936.

CleanEx

HS_UCHL1.

GermOnline

ENSG00000154277. Homo sapiens.

Family and domain databases

InterPro

IPR001578. Peptidase_C12.
[Graphical view]

Gene3D

G3DSA:3.40.532.10. Peptidase_C12. 1 hit.

PANTHER

PTHR10589. Peptidase_C12. 1 hit.

Pfam

PF01088. Peptidase_C12. 1 hit.
[Graphical view]

PRINTS

PR00707. UBCTHYDRLASE.

ProDom

PD350662. Peptidase_C12. 1 hit.
[Graphical view] [Entries sharing at least one domain]

PROSITE

PS00140. UCH_1. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

28756.

SOURCE

Search...

Entry information

Entry name

UCHL1_HUMAN

Accession

Primary (citable) accession number: P09936
Secondary accession number(s): Q4W5K6, Q71UM0

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	November 1, 1990
Last modified:	July 7, 2009
This is version 114 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)