Ubiquitin carboxy-terminal hydrolase L1 explained

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

Ubiquitin Carboxy-terminal Hydrolase L1 (UCH-L1)

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.^{[1] [2]}

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.^[3]

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.^{[4] [5]}

Furthermore, a polymorphism (S18Y) in this gene has been found to be associated with a reduced risk for Parkinson's disease.^[6] This polymorphism has specifically been shown to have antioxidant activity.^[7]

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.^[8]

The gene is also associated with Alzheimer's disease, and required for normal synaptic and cognitive function.^[9] 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.^[10]

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.^[11]

Ectopic expression

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.^[12] This abnormal expression of UCH-L1 is implicated in cancer and has led to the designation of UCH-L1 as an oncogene.^[13] Furthermore there is evidence that UCH-L1 might play a role in the pathogenesis of membranous glomerulonephritis as UCH-L1 de novo expression in podocytes was seen in PHN, the rat model of human mGN.^[14] This UCH-L1 expression is thought to induce at least in part podocyte hypertrophy.^[15]

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.^{[16] [17]}

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. The S18Y polymorphism of UCH-L1 has been shown to be less-prone to dimerization.^[8]

Interactions

Ubiquitin carboxy-terminal hydrolase L1 has been shown to interact with COP9 constitutive photomorphogenic homolog subunit 5.^[18]

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.^[19]

Most recently, UCH-L1 has been demonstrated to interact with the E3 ligase, parkin. Parkin has been demonstrated to bind and ubiquitinylate UCH-L1 to promote lysosomal degradation of UCH-L1.^[20]

See also

• Ubiquitin carboxyl-terminal esterase L3—the gene UCHL3
• Alpha synuclein
• Parkinson disease
• Proteasome

Further reading

• Healy DG, Abou-Sleiman PM, Wood NW . Genetic causes of Parkinson's disease: UCHL-1 . Cell and Tissue Research . 318 . 1 . 189–94 . Oct 2004 . 15221445 . 10.1007/s00441-004-0917-3 . 22530636 .
• Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J . Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes . Electrophoresis . 13 . 12 . 960–9 . Dec 1992 . 1286667 . 10.1002/elps.11501301199 . 41855774 .
• Edwards YH, Fox MF, Povey S, Hinks LJ, Thompson RJ, Day IN . 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 . Oct 1991 . 1840236 . 10.1111/j.1469-1809.1991.tb00853.x . 25763146 .
• Honoré B, Rasmussen HH, Vandekerckhove J, Celis JE . 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 . Mar 1991 . 1849484 . 10.1016/0014-5793(91)80300-R . 40473683 .
• Day IN, Hinks LJ, Thompson RJ . 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 . Jun 1990 . 2163617 . 1131465 . 10.1042/bj2680521.
• Day IN, Thompson RJ . 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 . Jan 1987 . 2947814 . 10.1016/0014-5793(87)81327-3 . 39218297 . free .
• Doran JF, Jackson P, Kynoch PA, Thompson RJ . 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 . Jun 1983 . 6343558 . 10.1111/j.1471-4159.1983.tb08124.x . 24386913 .
• Onno M, Nakamura T, Mariage-Samson R, Hillova J, Hill M . Human TRE17 oncogene is generated from a family of homologous polymorphic sequences by single-base changes . DNA and Cell Biology . 12 . 2 . 107–18 . Mar 1993 . 8471161 . 10.1089/dna.1993.12.107 .
• Larsen CN, Price JS, Wilkinson KD . Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active site residues . Biochemistry . 35 . 21 . 6735–44 . May 1996 . 8639624 . 10.1021/bi960099f .
• Best CL, Pudney J, Welch WR, Burger N, Hill JA . Localization and characterization of white blood cell populations within the human ovary throughout the menstrual cycle and menopause . Human Reproduction . 11 . 4 . 790–7 . Apr 1996 . 8671330 . 10.1093/oxfordjournals.humrep.a019256 . free .
• 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 . The immunolocalization of PGP 9.5 in normal human kidney and renal cell carcinoma . Il Giornale di Chirurgia . 18 . 10 . 521–4 . Oct 1997 . 9435142 .
• Larsen CN, Krantz BA, Wilkinson KD . Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases . Biochemistry . 37 . 10 . 3358–68 . Mar 1998 . 9521656 . 10.1021/bi972274d .
• 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 . The ubiquitin pathway in Parkinson's disease . Nature . 395 . 6701 . 451–2 . Oct 1998 . 9774100 . 10.1038/26652 . 1998Natur.395..451L . 204997455 .
• Wada H, Kito K, Caskey LS, Yeh ET, Kamitani T . Cleavage of the C-terminus of NEDD8 by UCH-L3 . Biochemical and Biophysical Research Communications . 251 . 3 . 688–92 . Oct 1998 . 9790970 . 10.1006/bbrc.1998.9532 .
• Leroy E, Boyer R, Polymeropoulos MH . Intron-exon structure of ubiquitin c-terminal hydrolase-L1 . DNA Research . 5 . 6 . 397–400 . Dec 1998 . 10048490 . 10.1093/dnares/5.6.397 . free .
• Lincoln S, Vaughan J, Wood N, Baker M, Adamson J, Gwinn-Hardy K, Lynch T, Hardy J, Farrer M . Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease . NeuroReport . 10 . 2 . 427–9 . Feb 1999 . 10203348 . 10.1097/00001756-199902050-00040 .
• 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 . 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 . Jul 1999 . 10454131 . 10.1016/S0304-3940(99)00465-6 . 26352360 .
• Saigoh K, Wang YL, Suh JG, Yamanishi T, Sakai Y, Kiyosawa H, Harada T, Ichihara N, Wakana S, Kikuchi T, Wada K . Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice . Nature Genetics . 23 . 1 . 47–51 . Sep 1999 . 10471497 . 10.1038/12647 . 34253163 .
• Mellick GD, Silburn PA . The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does not confer protection against idiopathic Parkinson's disease . Neuroscience Letters . 293 . 2 . 127–30 . Oct 2000 . 11027850 . 10.1016/S0304-3940(00)01510-X . 25234210 .
• Sharma N, McLean PJ, Kawamata H, Irizarry MC, Hyman BT . Alpha-synuclein has an altered conformation and shows a tight intermolecular interaction with ubiquitin in Lewy bodies . Acta Neuropathologica . 102 . 4 . 329–34 . Oct 2001 . 11603807 . 10.1007/s004010100369 . 33892290 .

Notes and References

1. Doran JF, Jackson P, Kynoch PA, Thompson RJ . 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 . Jun 1983 . 6343558 . 10.1111/j.1471-4159.1983.tb08124.x . 24386913 .
2. Web site: Entrez Gene: UCHL1 ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase).
3. Das C, Hoang QQ, Kreinbring CA, Luchansky SJ, Meray RK, Ray SS, Lansbury PT, Ringe D, Petsko GA . Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1 . Proceedings of the National Academy of Sciences of the United States of America . 103 . 12 . 4675–80 . Mar 2006 . 16537382 . 10.1073/pnas.0510403103 . 1450230. 2006PNAS..103.4675D . free .
4. 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 . The ubiquitin pathway in Parkinson's disease . Nature . 395 . 6701 . 451–2 . Oct 1998 . 9774100 . 10.1038/26652 . 1998Natur.395..451L . 204997455 .
5. 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 . 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 . Jul 1999 . 10454131 . 10.1016/s0304-3940(99)00465-6 . 26352360 .
6. Wang J, Zhao CY, Si YM, Liu ZL, Chen B, Yu L . ACT and UCH-L1 polymorphisms in Parkinson's disease and age of onset . Movement Disorders . 17 . 4 . 767–71 . Jul 2002 . 12210873 . 10.1002/mds.10179 . 23026015 .
7. Kyratzi E, Pavlaki M, Stefanis L . The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells . Human Molecular Genetics . 17 . 14 . 2160–71 . Jul 2008 . 18411255 . 10.1093/hmg/ddn115 . free .
8. 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 . Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron . Human Molecular Genetics . 12 . 16 . 1945–58 . Aug 2003 . 12913066 . 10.1093/hmg/ddg211 . free .
9. Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O . Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory . Cell . 126 . 4 . 775–88 . Aug 2006 . 16923396 . 10.1016/j.cell.2006.06.046 . 10916274 . free .
10. Chu KY, Li H, Wada K, Johnson JD . Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions . Diabetologia . 55 . 1 . 128–40 . Jan 2012 . 22038515 . 10.1007/s00125-011-2323-1 . free .
11. Bilguvar K, Tyagi NK, Ozkara C, Tuysuz B, Bakircioglu M, Choi M, Delil S, Caglayan AO, Baranoski JF, Erturk O, Yalcinkaya C, Karacorlu M, Dincer A, Johnson MH, Mane S, Chandra SS, Louvi A, Boggon TJ, Lifton RP, Horwich AL, Gunel M . Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration . Proceedings of the National Academy of Sciences of the United States of America . 110 . 9 . 3489–94 . Feb 2013 . 23359680 . 10.1073/pnas.1222732110 . 3587195. 2013PNAS..110.3489B . free .
12. Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J, Yeh LA, Cuny GD, Stein RL, Lansbury PT . Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line . Chemistry & Biology . 10 . 9 . 837–46 . Sep 2003 . 14522054 . 10.1016/j.chembiol.2003.08.010 . free .
13. Hussain S, Foreman O, Perkins SL, Witzig TE, Miles RR, van Deursen J, Galardy PJ . 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 . Sep 2010 . 20574456 . 3236611 . 10.1038/leu.2010.138 .
14. Meyer-Schwesinger C, Meyer TN, Münster S, Klug P, Saleem M, Helmchen U, Stahl RA . A new role for the neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) in podocyte process formation and podocyte injury in human glomerulopathies . The Journal of Pathology . 217 . 3 . 452–64 . Feb 2009 . 18985619 . 10.1002/path.2446 . 23851206 .
15. Lohmann F, Sachs M, Meyer TN, Sievert H, Lindenmeyer MT, Wiech T, Cohen CD, Balabanov S, Stahl RA, Meyer-Schwesinger C . UCH-L1 induces podocyte hypertrophy in membranous nephropathy by protein accumulation . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1842 . 7 . 945–58 . Jul 2014 . 24583340 . 10.1016/j.bbadis.2014.02.011 .
16. Web site: Peterson . Ivars . Knots in proteins . Science News . 2006-10-14 . 2008-09-11 . https://web.archive.org/web/20080421150458/http://www.sciencenews.org/articles/20061014/mathtrek.asp . 2008-04-21.
17. Virnau P, Mirny LA, Kardar M . Intricate knots in proteins: Function and evolution . PLOS Computational Biology . 2 . 9 . e122 . Sep 2006 . 16978047 . 1570178 . 10.1371/journal.pcbi.0020122 . 2006PLSCB...2..122V . free .
18. Caballero OL, Resto V, Patturajan M, Meerzaman D, Guo MZ, Engles J, Yochem R, Ratovitski E, Sidransky D, Jen J . Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1) . Oncogene . 21 . 19 . 3003–10 . May 2002 . 12082530 . 10.1038/sj.onc.1205390 . 20004395 .
19. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT . The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility . Cell . 111 . 2 . 209–18 . Oct 2002 . 12408865 . 10.1016/s0092-8674(02)01012-7 . 6849108 . free .
20. McKeon JE, Sha D, Li L, Chin LS . Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system . Cellular and Molecular Life Sciences . 72 . 9 . 1811–24 . May 2015 . 25403879 . 10.1007/s00018-014-1781-2 . 4395523.