Reviewed,
UniProtKB/Swiss-Prot P09936 (UCHL1_HUMAN)
Last modified
July 7, 2009.
Version 114.
History...
Clusters with 100%,
90%,
50% identity |
Documents (7) |
Third-party data |
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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 |
| ||
| 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 | |
| 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 processInferred 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 activityInferred from electronic annotation. Source: UniProtKB-KW omega peptidase activityInferred from direct assay. Source: UniProtKB ubiquitin bindingInferred from direct assay. Source: UniProtKB ubiquitin thiolesterase activityTraceable 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 | ||||||||||||||||||||||||||||||||||||||||||
Helix Strand Turn | ||||||||||||||||||||||||||||||||||||||||||
| 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
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References
| « Hide '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. 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. 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. |
Cross-references
Sequence databases | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 AF076272 Genomic DNA. Translation: AAD09172.1. | |||||||||||||
| IPI | IPI00018352. | ||||||||||||
| PIR | A25856. | ||||||||||||
| RefSeq | NP_004172.2. | ||||||||||||
| UniGene | Hs.518731 | ||||||||||||
3D structure databases | |||||||||||||
| |||||||||||||
| 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 |
| ||||||||
| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | HPI (Human Proteome Initiative) | ||||||||
Relevant documents
| Human chromosome 4 Human chromosome 4: entries, gene names and cross-references to MIM |
| Human entries with polymorphisms or disease mutations List of human entries with polymorphisms or disease mutations |
| Human polymorphisms and disease mutations Index of human polymorphisms and disease mutations |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| PDB cross-references Index of Protein Data Bank (PDB) cross-references |
| Peptidase families Classification of peptidase families and list of entries |
| SIMILARITY comments Index of protein domains and families |

Clusters with


