Ubiquitin carboxy-terminal hydrolase L1

Last updated
UCHL1
Protein UCHL1 PDB 2etl.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases UCHL1 , HEL-117, NDGOA, PARK5, PGP 9.5, PGP9.5, PGP95, Uch-L1, HEL-S-53, ubiquitin C-terminal hydrolase L1, SPG79, UCHL-1
External IDs OMIM: 191342 MGI: 103149 HomoloGene: 37894 GeneCards: UCHL1
Orthologs
SpeciesHumanMouse
Entrez

7345

22223

Ensembl

ENSG00000154277

ENSMUSG00000029223

UniProt

P09936

Q9R0P9

RefSeq (mRNA)

NM_004181

NM_011670

RefSeq (protein)

NP_004172

NP_035800

Location (UCSC) Chr 4: 41.26 – 41.27 Mb Chr 5: 66.83 – 66.84 Mb
PubMed search [3] [4]
Wikidata
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.

Contents

Ubiquitin Carboxy-terminal Hydrolase L1 (UCH-L1)
Chk-UCH1-GFAP-20X-1.jpg
Neurons from rat brain tissue stained green with antibody to ubiquitin C-terminal hydrolase L1 (UCH-L1) which highlights the cell body strongly and the cell processes more weakly. 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 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. [12]

The gene is also associated with Alzheimer's disease, and required for normal synaptic and cognitive function. [13] 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. [14]

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 neurons and testis/ovary tissue, it has been found to be expressed in certain lung-tumor cell lines. [16] This abnormal expression of UCH-L1 is implicated in cancer and has led to the designation of UCH-L1 as an oncogene. [17] 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. [18] This UCH-L1 expression is thought to induce at least in part podocyte hypertrophy. [19]

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 interact with COP9 constitutive photomorphogenic homolog subunit 5. [23]

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. [22]

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. [24]

See also

Related Research Articles

<span class="mw-page-title-main">Lewy body</span> Spherical inclusion commonly found in damaged neurons

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).

<span class="mw-page-title-main">Alpha-synuclein</span> Protein found in humans

Alpha-synuclein(aSyn) is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.

<span class="mw-page-title-main">Parkin (protein)</span>

Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ATP-dependent process. Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.

<span class="mw-page-title-main">Deubiquitinating enzyme</span>

Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.

UBB+1 is shorthand for Ubiquitin-B+1, a frameshifted mutant arising from the Ubiquitin B gene. UBB+1 is thought to arise from molecular misreading, a poorly understood process. Molecular misreading introduces dinucleotide deletions into mRNA transcripts. These deletions are not present in genomic DNA. UBB+1 has been observed in the hallmarks of Alzheimer's disease, as well as other tauopathies and in polyglutamine diseases but not in synucleinopathies. Since its discovery it has been shown in vitro and in vivo that UBB+1 inhibits the proteasome and gives rise to downstream effects. In non-neuronal cells UBB+1 also accumulates suggesting a functional role in non-neuronal diseases. UBB+1 can be truncated by yeast's ubiquitin hydrolase 1 (YUH1) and ubiquitin C-terminal hydrolase L3 UCHL3 even though the glycine at position 76 has been substituted for a tyrosine.

Cyclopentenone prostaglandins are a subset of prostaglandins (PGs) or prostanoids that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated cyclopentenone structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.

<span class="mw-page-title-main">Beta-synuclein</span> Protein-coding gene in the species Homo sapiens

Beta-synuclein is a protein that in humans is encoded by the SNCB gene.

<span class="mw-page-title-main">Gamma-synuclein</span> Protein-coding gene in the species Homo sapiens

Gamma-synuclein is a protein that in humans is encoded by the SNCG gene.

<span class="mw-page-title-main">LRRK2</span> Protein kinase found in humans

Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin and PARK8, is a large, multifunctional kinase enzyme that in humans is encoded by the LRRK2 gene. LRRK2 is a member of the leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease and Crohn's disease.

<span class="mw-page-title-main">DJ-1</span> Protein-coding gene found in humans

Protein deglycase DJ-1, also known as Parkinson disease protein 7, is a protein which in humans is encoded by the PARK7 gene.

<span class="mw-page-title-main">GPR37</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 37 is a protein that in humans is encoded by the GPR37 gene.

<span class="mw-page-title-main">SNCAIP</span> Protein-coding gene in the species Homo sapiens

Synphilin-1 is a protein that in humans is encoded by the SNCAIP gene. SNCAIP stands for "synuclein, alpha interacting protein" and can be signified by SNCAP_HUMAN, synphilin 1, synuclein, alpha interacting protein (synphilin), and SYPH1.

<span class="mw-page-title-main">SMURF1</span> Mammalian protein found in Homo sapiens

E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the SMURF1 gene. The SMURF1 Gene encodes a protein with a size of 757 amino acids and the molecular mass of this protein is 86114 Da.

<span class="mw-page-title-main">USP7</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene.

<span class="mw-page-title-main">Ubiquitin carboxyl-terminal hydrolase L5</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase isozyme L5 is an enzyme that in humans is encoded by the UCHL5 gene.

<span class="mw-page-title-main">UCHL3</span> Enzyme in humans encoded by the UCHL3 gene

Ubiquitin carboxyl-terminal hydrolase isozyme L3 is an enzyme that in humans is encoded by the UCHL3 gene.

<span class="mw-page-title-main">BAP1</span> Protein-coding gene in the species Homo sapiens

BRCA1 associated protein-1 is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene. BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity. Recent studies have shown that BAP1 and its fruit fly homolog, Calypso, are members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.

<span class="mw-page-title-main">USP20</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.

Parkinson's disease (PD) is a degenerative disorder of the central nervous system. Most people with PD have idiopathic Parkinson's disease. A small proportion of cases, however, can be attributed to known genetic factors. Other factors such as environmental toxins, herbicides, pesticides, and fungicides, have been associated with the risk of developing PD, but no causal relationships have been proven.

Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000154277 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029223 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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. doi:10.1111/j.1471-4159.1983.tb08124.x. PMID   6343558. S2CID   24386913.
  6. ↑ "Entrez Gene: UCHL1 ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)".
  7. ↑ Das C, Hoang QQ, Kreinbring CA, Luchansky SJ, Meray RK, Ray SS, Lansbury PT, Ringe D, Petsko GA (Mar 2006). "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. Bibcode:2006PNAS..103.4675D. doi: 10.1073/pnas.0510403103 . PMC   1450230 . PMID   16537382.
  8. ↑ 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. Bibcode:1998Natur.395..451L. doi:10.1038/26652. PMID   9774100. S2CID   204997455.
  9. ↑ 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. doi:10.1016/s0304-3940(99)00465-6. PMID   10454131. S2CID   26352360.
  10. ↑ Wang J, Zhao CY, Si YM, Liu ZL, Chen B, Yu L (Jul 2002). "ACT and UCH-L1 polymorphisms in Parkinson's disease and age of onset". Movement Disorders. 17 (4): 767–71. doi:10.1002/mds.10179. PMID   12210873. S2CID   23026015.
  11. ↑ Kyratzi E, Pavlaki M, Stefanis L (Jul 2008). "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells". Human Molecular Genetics. 17 (14): 2160–71. doi: 10.1093/hmg/ddn115 . PMID   18411255.
  12. 1 2 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 (Aug 2003). "Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron". Human Molecular Genetics. 12 (16): 1945–58. doi: 10.1093/hmg/ddg211 . PMID   12913066.
  13. ↑ Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (Aug 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. S2CID   10916274.
  14. ↑ Chu KY, Li H, Wada K, Johnson JD (Jan 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.
  15. ↑ 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 (Feb 2013). "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. Bibcode:2013PNAS..110.3489B. doi: 10.1073/pnas.1222732110 . PMC   3587195 . PMID   23359680.
  16. ↑ Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J, Yeh LA, Cuny GD, Stein RL, Lansbury PT (Sep 2003). "Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line". Chemistry & Biology. 10 (9): 837–46. doi: 10.1016/j.chembiol.2003.08.010 . PMID   14522054.
  17. ↑ Hussain S, Foreman O, Perkins SL, Witzig TE, Miles RR, van Deursen J, Galardy PJ (Sep 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.
  18. ↑ Meyer-Schwesinger C, Meyer TN, Münster S, Klug P, Saleem M, Helmchen U, Stahl RA (Feb 2009). "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. doi:10.1002/path.2446. PMID   18985619. S2CID   23851206.
  19. ↑ Lohmann F, Sachs M, Meyer TN, Sievert H, Lindenmeyer MT, Wiech T, Cohen CD, Balabanov S, Stahl RA, Meyer-Schwesinger C (Jul 2014). "UCH-L1 induces podocyte hypertrophy in membranous nephropathy by protein accumulation". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842 (7): 945–58. doi:10.1016/j.bbadis.2014.02.011. PMID   24583340.
  20. ↑ Peterson, Ivars (2006-10-14). "Knots in proteins". Science News. Archived from the original on 2008-04-21. Retrieved 2008-09-11.
  21. ↑ Virnau P, Mirny LA, Kardar M (Sep 2006). "Intricate knots in proteins: Function and evolution". PLOS Computational Biology. 2 (9): e122. Bibcode:2006PLSCB...2..122V. doi:10.1371/journal.pcbi.0020122. PMC   1570178 . PMID   16978047.
  22. 1 2 Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT (Oct 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. doi: 10.1016/s0092-8674(02)01012-7 . PMID   12408865. S2CID   6849108.
  23. ↑ 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.
  24. ↑ McKeon JE, Sha D, Li L, Chin LS (May 2015). "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. doi:10.1007/s00018-014-1781-2. PMC   4395523 . PMID   25403879.

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