関: ubiquitin C-terminal hydrolase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/03/11 10:50:44」(JST)

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Ubiquitin carboxy-terminal hydrolase L1 (EC 3.1.2.15, ubiquitin C-terminal hydrolase, UCH-L1) is a deubiquitinating enzyme.

Function[edit]

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.^[1]^[2]

Relevance to neurodegenerative disorders[edit]

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^[3]^[4]

Furthermore, a polymorphism (S18Y) in this gene has been found to be associated with a reduced risk for Parkinson's disease. This polymorphism has specifically been shown to have antioxidant activity.^[5]

Another potentially protective function of UCH-L1 is its reported ability to stabilize monoubiquitin, an important component of the ubiquitin proteasome system. It is thought that by stabilizing the monomers of ubiquitin and thereby preventing their degradation, UCH-L1 increases the available pool of ubiquitin to be tagged onto proteins destined to be degraded by the proteasome.^[6]

The gene is also associated with the Alzheimer's disease, and required for normal synaptic and cognitive function.^[7] Loss of Uchl1 increases the susceptibility of pancreatic beta-cells to programmed cell death, indicating that this protein plays a protective role in neuroendocrine cells and illustrating a link between diabetes and neurodegenerative diseases.^[8]

Ectopic expression[edit]

Although UCH-L1 protein expression is specific to neurons and testis/ovary tissue, it has been found to be expressed in certain lung-tumor cell lines.^[9] This abnormal expression of UCH-L1 is implicated in cancer and has lead to the designation of UCH-L1 as an oncogene.^[10]

Protein structure[edit]

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.^[11]^[12]

Interactions[edit]

Ubiquitin carboxy-terminal hydrolase L1 has been shown to interact with COP9 constitutive photomorphogenic homolog subunit 5.^[13]

UCH-L1 has also been shown to interact with α-synuclein, another protein implicated in the pathology of Parkinson disease. This activity is reported to be the result of its ubiquityl ligase activity which may be associated with the I93M pathogenic mutation in the gene.^[14]

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.^[14] The S18Y polymorphism of UCH-L1 has been shown to be less-prone to dimerization.^[6]

References[edit]

^ Doran JF, Jackson P, Kynoch PA, Thompson RJ (June 1983). "Isolation of PGP 9.5, a new human neurone-specific protein detected by high-resolution two-dimensional electrophoresis". J. Neurochem. 40 (6): 1542–1547. doi:10.1111/j.1471-4159.1983.tb08124.x. PMID 6343558.
^ "Entrez Gene: UCHL1 ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)".
^ 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 (October 1998). "The ubiquitin pathway in Parkinson's disease". Nature 395 (6701): 451–2. doi:10.1038/26652. PMID 9774100.
^ 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 (July 1999). "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease". Neurosci. Lett. 270 (1): 1–4. PMID 10454131.
^ Kyratzi E, Pavlaki M, Stefanis L (July 2008). "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells". Hum. Mol. Genet. 17 (14): 2160–71. doi:10.1093/hmg/ddn115. PMID 18411255.
^ ^a ^b Osaka H, Wang YL, Takada K, Takizawa S, Setsuie R, Li H, Sato Y, Nishikawa K, Sun YJ, Sakurai M, Harada T, Hara Y, Kimura I, Chiba S, Namikawa K, Kiyama H, Noda M, Aoki S, Wada K (August 2003). "Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron". Hum. Mol. Genet. 12 (16): 1945–58. PMID 12913066.
^ Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (August 2006). "Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory". Cell 126 (4): 775–88. doi:10.1016/j.cell.2006.06.046. PMID 16923396.
^ Chu KY, Li H, Wada K, Johnson JD (January 2012). "Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions". Diabetologia 55 (1): 128–40. doi:10.1007/s00125-011-2323-1. PMID 22038515.
^ Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J, Yeh LA, Cuny GD, Stein RL, Lansbury PT (September 2003). "Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line". Chem. Biol. 10 (9): 837–46. PMID 14522054.
^ Hussain S, Foreman O, Perkins SL, Witzig TE, Miles RR, van Deursen J, Galardy PJ (September 2010). "The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling". Leukemia 24 (9): 1641–55. doi:10.1038/leu.2010.138. PMC 3236611. PMID 20574456.
^ Peterson, Ivars (2006-10-14). "Knots in proteins". Science News. Archived from the original on 2008-04-21. Retrieved 2008-09-11.
^ Virnau P, Mirny LA, Kardar M (September 2006). "Intricate knots in proteins: Function and evolution". PLoS Comput. Biol. 2 (9): e122. doi:10.1371/journal.pcbi.0020122. PMC 1570178. PMID 16978047.
^ Caballero OL, Resto V, Patturajan M, Meerzaman D, Guo MZ, Engles J, Yochem R, Ratovitski E, Sidransky D, Jen J (May 2002). "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)". Oncogene 21 (19): 3003–10. doi:10.1038/sj.onc.1205390. PMID 12082530.
^ ^a ^b Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT (October 2002). "The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility". Cell 111 (2): 209–18. PMID 12408865.

External links[edit]

Ubiquitin Carboxy-Terminal Hydrolase at the US National Library of Medicine Medical Subject Headings (MeSH)

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「ubiquitin C-terminal hydrolase」

Ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)
	; PDB rendering based on 2etl.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2ETL, 2LEN, 3IFW, 3IRT, 3KVF, 3KW5, 4DM9
Identifiers
Symbols	UCHL1 (; PARK5; PGP 9.5; PGP9.5; PGP95; Uch-L1)
External IDs	OMIM: 191342 MGI: 103149 HomoloGene: 37894 ChEMBL: 6159 GeneCards: UCHL1 Gene
EC number	3.4.19.12
Gene Ontology
Molecular function	• cysteine-type endopeptidase activity; • ubiquitin thiolesterase activity; • protein binding; • omega peptidase activity; • ligase activity; • alpha-2A adrenergic receptor binding; • ubiquitin binding;
Cellular component	• nucleus; • nucleolus; • cytoplasm; • endoplasmic reticulum membrane; • cytosol; • plasma membrane; • axon; • neuronal cell body;
Biological process	• ubiquitin-dependent protein catabolic process; • response to stress; • axon target recognition; • adult walking behavior; • cell death; • cell proliferation; • protein deubiquitination; • sensory perception of pain; • axon transport of mitochondrion; • eating behavior; • negative regulation of MAP kinase activity; • muscle fiber development; • neuromuscular process;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

ユビキチンC末端加水分解酵素、ユビキチンC末端ヒドロラーゼ

関: ubiquitin thiolesterase

「ユビキチンチオエステラーゼ」

　　[★]

英: ubiquitin thiolesterase
関: ユビキチンC末端ヒドロラーゼ

[1] Doran JF, Jackson P, Kynoch PA, Thompson RJ (June 1983). "Isolation of PGP 9.5, a new human neurone-specific protein detected by high-resolution two-dimensional electrophoresis". J. Neurochem. 40 (6): 1542–1547. doi:10.1111/j.1471-4159.1983.tb08124.x. PMID 6343558.

[entrez-2] "Entrez Gene: UCHL1 ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)".

[pmid9774100-3] 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 (October 1998). "The ubiquitin pathway in Parkinson's disease". Nature 395 (6701): 451–2. doi:10.1038/26652. PMID 9774100.

[pmid10454131-4] 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 (July 1999). "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease". Neurosci. Lett. 270 (1): 1–4. PMID 10454131.

[pmid18411255-5] Kyratzi E, Pavlaki M, Stefanis L (July 2008). "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells". Hum. Mol. Genet. 17 (14): 2160–71. doi:10.1093/hmg/ddn115. PMID 18411255.

[pmid12913066-6] Osaka H, Wang YL, Takada K, Takizawa S, Setsuie R, Li H, Sato Y, Nishikawa K, Sun YJ, Sakurai M, Harada T, Hara Y, Kimura I, Chiba S, Namikawa K, Kiyama H, Noda M, Aoki S, Wada K (August 2003). "Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron". Hum. Mol. Genet. 12 (16): 1945–58. PMID 12913066.

[pmid16923396-7] Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (August 2006). "Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory". Cell 126 (4): 775–88. doi:10.1016/j.cell.2006.06.046. PMID 16923396.

[pmid22038515-8] Chu KY, Li H, Wada K, Johnson JD (January 2012). "Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions". Diabetologia 55 (1): 128–40. doi:10.1007/s00125-011-2323-1. PMID 22038515.

[pmid14522054-9] Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J, Yeh LA, Cuny GD, Stein RL, Lansbury PT (September 2003). "Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line". Chem. Biol. 10 (9): 837–46. PMID 14522054.

[pmid20574456-10] Hussain S, Foreman O, Perkins SL, Witzig TE, Miles RR, van Deursen J, Galardy PJ (September 2010). "The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling". Leukemia 24 (9): 1641–55. doi:10.1038/leu.2010.138. PMC 3236611. PMID 20574456.

[11] Peterson, Ivars (2006-10-14). "Knots in proteins". Science News. Archived from the original on 2008-04-21. Retrieved 2008-09-11.

[pmid16978047-12] Virnau P, Mirny LA, Kardar M (September 2006). "Intricate knots in proteins: Function and evolution". PLoS Comput. Biol. 2 (9): e122. doi:10.1371/journal.pcbi.0020122. PMC 1570178. PMID 16978047.

[pmid12082530-13] Caballero OL, Resto V, Patturajan M, Meerzaman D, Guo MZ, Engles J, Yochem R, Ratovitski E, Sidransky D, Jen J (May 2002). "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)". Oncogene 21 (19): 3003–10. doi:10.1038/sj.onc.1205390. PMID 12082530.

[pmid12408865-14] Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT (October 2002). "The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility". Cell 111 (2): 209–18. PMID 12408865.

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ubiquitin thiolesterase