Ubiquitin carboxy-terminal hydrolase L1
Ensembl | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 4: 41.26 – 41.27 Mb | Chr 5: 66.83 – 66.84 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Ubiquitin carboxy-terminal hydrolase L1 (EC 3.1.2.15, ubiquitin C-terminal hydrolase, UCH-L1) is a deubiquitinating enzyme.
| Ubiquitin Carboxy-terminal Hydrolase L1 (UCH-L1) | |
|---|---|
Astrocytes are stained in red with antibody to the GFAP protein found in cytoplasmic filaments. Nuclei of all cell types are stained blue with a DNA binding dye. Antibodies, cell preparation and image generated by EnCor Biotechnology Inc. | |
| Anatomical terms of microanatomy] |
Function
UCH-L1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCH-L1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. It is abundantly present in all neurons (accounts for 1-2% of total brain protein), expressed specifically in neurons and testis/ovary.[5][6]
The catalytic triad of UCH-L1 contains a cysteine at position 90, an aspartate at position 176, and a histidine at position 161 that are responsible for its hydrolase activity.[7]
Relevance to neurodegenerative disorders
A point mutation (I93M) in the gene encoding this protein is implicated as the cause of Parkinson's disease in one German family, although this finding is controversial, as no other Parkinson's disease patients with this mutation have been found.[8][9]
Furthermore, a polymorphism (S18Y) in this gene has been found to be associated with a reduced risk for Parkinson's disease.[10] This polymorphism has specifically been shown to have antioxidant activity.[11]
Another potentially protective function of UCH-L1 is its reported ability to stabilize mono
The gene is also associated with
Patients with early-onset neurodegeneration in which the causative mutation was in the UCHL1 gene (specifically, the ubiquitin binding domain, E7A) display blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and upper motor neuron dysfunction.[15]
Ectopic expression
Although UCH-L1 protein expression is specific to
Protein structure
Human UCH-L1 and the closely related protein UCHL3 have one of the most complicated knot structure yet discovered for a protein, with five knot crossings. It is speculated that a knot structure may increase a protein's resistance to degradation in the proteasome.[20][21]
The conformation of the UCH-L1 protein may also be an important indication of neuroprotection or pathology. For example, the UCH-L1 dimer has been shown to exhibit the potentially pathogenic ligase activity and may lead to the aforementioned increase in aggregation of α-synuclein.[22] The S18Y polymorphism of UCH-L1 has been shown to be less-prone to dimerization.[12]
Interactions
Ubiquitin carboxy-terminal hydrolase L1 has been shown to
UCH-L1 has also been shown to interact with
Most recently, UCH-L1 has been demonstrated to interact with the E3 ligase,
See also
- Ubiquitin carboxyl-terminal esterase L3—the gene UCHL3
- Alpha synuclein
- Parkinson disease
- Proteasome
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000154277 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029223 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 24386913.
- ^ "Entrez Gene: UCHL1 ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)".
- PMID 16537382.
- S2CID 204997455.
- S2CID 26352360.
- S2CID 23026015.
- PMID 18411255.
- ^ PMID 12913066.
- S2CID 10916274.
- PMID 22038515.
- PMID 23359680.
- PMID 14522054.
- PMID 20574456.
- S2CID 23851206.
- PMID 24583340.
- ^ Peterson, Ivars (2006-10-14). "Knots in proteins". Science News. Archived from the original on 2008-04-21. Retrieved 2008-09-11.
- PMID 16978047.
- ^ S2CID 6849108.
- S2CID 20004395.
- PMID 25403879.
Further reading
- Healy DG, Abou-Sleiman PM, Wood NW (Oct 2004). "Genetic causes of Parkinson's disease: UCHL-1". Cell and Tissue Research. 318 (1): 189–94. S2CID 22530636.
- Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J (Dec 1992). "Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes". Electrophoresis. 13 (12): 960–9. S2CID 41855774.
- Edwards YH, Fox MF, Povey S, Hinks LJ, Thompson RJ, Day IN (Oct 1991). "The gene for human neurone specific ubiquitin C-terminal hydrolase (UCHL1, PGP9.5) maps to chromosome 4p14". Annals of Human Genetics. 55 (Pt 4): 273–8. S2CID 25763146.
- Honoré B, Rasmussen HH, Vandekerckhove J, Celis JE (Mar 1991). "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". FEBS Letters. 280 (2): 235–40. S2CID 40473683.
- Day IN, Hinks LJ, Thompson RJ (Jun 1990). "The structure of the human gene encoding protein gene product 9.5 (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase". The Biochemical Journal. 268 (2): 521–4. PMID 2163617.
- Day IN, Thompson RJ (Jan 1987). "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel cytoplasmic marker for neurones and neuroendocrine cells". FEBS Letters. 210 (2): 157–60. S2CID 39218297.
- Doran JF, Jackson P, Kynoch PA, Thompson RJ (Jun 1983). "Isolation of PGP 9.5, a new human neurone-specific protein detected by high-resolution two-dimensional electrophoresis". Journal of Neurochemistry. 40 (6): 1542–7. S2CID 24386913.
- Onno M, Nakamura T, Mariage-Samson R, Hillova J, Hill M (Mar 1993). "Human TRE17 oncogene is generated from a family of homologous polymorphic sequences by single-base changes". DNA and Cell Biology. 12 (2): 107–18. PMID 8471161.
- Larsen CN, Price JS, Wilkinson KD (May 1996). "Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active site residues". Biochemistry. 35 (21): 6735–44. PMID 8639624.
- Best CL, Pudney J, Welch WR, Burger N, Hill JA (Apr 1996). "Localization and characterization of white blood cell populations within the human ovary throughout the menstrual cycle and menopause". Human Reproduction. 11 (4): 790–7. PMID 8671330.
- D'Andrea V, Malinovsky L, Berni A, Biancari F, Biassoni L, Di Matteo FM, Corbellini L, Falvo L, Santoni F, Spyrou M, De Antoni E (Oct 1997). "The immunolocalization of PGP 9.5 in normal human kidney and renal cell carcinoma". Il Giornale di Chirurgia. 18 (10): 521–4. PMID 9435142.
- Larsen CN, Krantz BA, Wilkinson KD (Mar 1998). "Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases". Biochemistry. 37 (10): 3358–68. PMID 9521656.
- Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (Oct 1998). "The ubiquitin pathway in Parkinson's disease". Nature. 395 (6701): 451–2. S2CID 204997455.
- Wada H, Kito K, Caskey LS, Yeh ET, Kamitani T (Oct 1998). "Cleavage of the C-terminus of NEDD8 by UCH-L3". Biochemical and Biophysical Research Communications. 251 (3): 688–92. PMID 9790970.
- Leroy E, Boyer R, Polymeropoulos MH (Dec 1998). "Intron-exon structure of ubiquitin c-terminal hydrolase-L1". DNA Research. 5 (6): 397–400. PMID 10048490.
- Lincoln S, Vaughan J, Wood N, Baker M, Adamson J, Gwinn-Hardy K, Lynch T, Hardy J, Farrer M (Feb 1999). "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease". NeuroReport. 10 (2): 427–9. PMID 10203348.
- Harhangi BS, Farrer MJ, Lincoln S, Bonifati V, Meco G, De Michele G, Brice A, Dürr A, Martinez M, Gasser T, Bereznai B, Vaughan JR, Wood NW, Hardy J, Oostra BA, Breteler MM (Jul 1999). "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease". Neuroscience Letters. 270 (1): 1–4. S2CID 26352360.
- Saigoh K, Wang YL, Suh JG, Yamanishi T, Sakai Y, Kiyosawa H, Harada T, Ichihara N, Wakana S, Kikuchi T, Wada K (Sep 1999). "Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice". Nature Genetics. 23 (1): 47–51. S2CID 34253163.
- Mellick GD, Silburn PA (Oct 2000). "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does not confer protection against idiopathic Parkinson's disease". Neuroscience Letters. 293 (2): 127–30. S2CID 25234210.
- Sharma N, McLean PJ, Kawamata H, Irizarry MC, Hyman BT (Oct 2001). "Alpha-synuclein has an altered conformation and shows a tight intermolecular interaction with ubiquitin in Lewy bodies". Acta Neuropathologica. 102 (4): 329–34. S2CID 33892290.
External links
- Ubiquitin+Carboxy-Terminal+Hydrolase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P09936 (Ubiquitin carboxyl-terminal hydrolase isozyme L1) at the PDBe-KB.
PDB gallery | |
|---|---|
|
