The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells

Kyratzi, Elli; Pavlaki, Maria; Stefanis, Leonidas

doi:10.1093/hmg/ddn115

Cited by 45 publications

(37 citation statements)

References 41 publications

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“…The authors of this report suggest that UCHL1 may increase ubiquitination (and hence behave as a ligase) of microtubule components (28). In light of these studies, and others that indicate that UCHL1 may have functions independent of the ubiquitin-proteasome system (29,30) and the misaligned active site observed in the structure of the apo form of the protein, the demonstration that UCHL1 can adopt a productive conformation as a hydrolase when bound to ubiquitin assumes particular significance.…”

Section: Al Demonstrating That Leu8 Of Ubiquitin Is Critically Requimentioning

confidence: 81%

Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation

Boudreaux

Maiti

Davies

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

104

120

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Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a Parkinson disease-associated, putative cysteine protease found abundantly and selectively expressed in neurons. The crystal structure of apo UCHL1 showed that the active-site residues are not aligned in a canonical form, with the nucleophilic cysteine being 7.7 Å from the general base histidine, an arrangement consistent with an inactive form of the enzyme. Here we report the crystal structures of the wild type and two Parkinson disease-associated variants of the enzyme, S18Y and I93M, bound to a ubiquitin-based suicide substrate, ubiquitin vinyl methyl ester. These structures reveal that ubiquitin vinyl methyl ester binds primarily at two sites on the enzyme, with its carboxy terminus at the active site and with its amino-terminal β-hairpin at the distal site-a surface-exposed hydrophobic crevice 17 Å away from the active site. Binding at the distal site initiates a cascade of side-chain movements in the enzyme that starts at a highly conserved, surface-exposed phenylalanine and is relayed to the active site resulting in the reorientation and proximal placement of the general base within 4 Å of the catalytic cysteine, an arrangement found in productive cysteine proteases. Mutation of the distal-site, surface-exposed phenylalanine to alanine reduces ubiquitin binding and severely impairs the catalytic activity of the enzyme. These results suggest that the activity of UCHL1 may be regulated by its own substrate.deubiquitinating enzyme | enzyme suicide substrate complex | neurodegeneration | ubiquitination U CHL1, a member of the UCH (ubiquitin C-terminal hydrolase) family of deubiquitinating enzymes (DUBs), is a 223-amino acid protein found abundantly and selectively expressed in brain, constituting up to 1-2% of total brain protein (1, 2). In vivo studies suggest that UCHL1 is involved in regulation of ubiquitin pool, apoptosis, and learning and memory, and its absence in mice because of spontaneous intragenic deletions yields phenotypes with neurological defects (3). Mutations in UCHL1 have been implicated in Parkinson disease (PD). A point mutation near the active site that changes Ile93 to Met (I93M) has been linked to an increased risk of developing an autosomaldominant form of PD (4). Conversely, a common S18Y polymorphism reduces susceptibility to PD (5, 6) and Alzheimer's disease (7). In addition to its association with neurodegenerative diseases, abnormal expression of UCHL1 is found in many forms of cancer, including lung, colorectal, and pancreatic cancers, and may be related to tumor progression (8, 9). The normal function of UCHL1, however, is not known. Also unknown are how the activity of this abundant neuronal enzyme is regulated and what its true physiological substrates are, although biochemical studies have indicated that UCHL1 can accept short-peptide (α or ϵ-amino-linked) or small-molecule C-terminal conjugates of ubiquitin as substrates, cleaving, as its name suggests, the amide bond following immediately after the C-terminal glycine (Gly7...

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Section: Al Demonstrating That Leu8 Of Ubiquitin Is Critically Requimentioning

confidence: 81%

Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation

Boudreaux

Maiti

Davies

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

104

120

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“…UCH-L1 may participate in apoptosis, ubiquitin homeostasis, long-term potentiation (54), chaperone-mediated autophagy (38), and protection against oxidative stress (15), but its role in these processes is not understood. The discovery and characterization of a membrane-associated and farnesylated form of UCH-L1 provide a new target for further investigation of UCH-L1's role in these phenomena.…”

Section: Discussionmentioning

confidence: 99%

“…An S18Y polymorphism in UCH-L1 reduces susceptibility to Parkinson's disease (PD) (8)(9)(10)(11)(12)) and Alzheimer's disease (AD) (13) and may influence the age at onset of Huntington's disease (14). A recent study suggests that the S18Y substitution may confer antioxidant function to UCH-L1 (15). The genetic association between UCH-L1 and AD is consistent with findings that transduction of soluble UCH-L1 protein into hippocampal slices treated with amyloid beta (A␤) restores synaptic function, and that transduction of UCH-L1 into a mouse model of AD rescues contextual memory deficits (16).…”

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confidence: 99%

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Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Liu

Meray

Grammatopoulos³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

127

131

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Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1 M ) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1 M in transfected cells is shown to correlate with the intracellular level of ␣-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1 M in cell culture models of ␣-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces ␣-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1 M , suggesting that it may negatively regulate the lysosomal degradation of ␣-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.farnesylation ͉ synuclein

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“…This protection may result from the reduced ligase activity caused by the mutation [73], but the mechanism is unclear. Another explanation may be that the S18Y variant functions as an antioxidant to protect neurons from oxidative damage [150]. This might imply that UCH-L1 could be used therapeutically to prevent neurodegeneration.…”

Section: Uch-l1mentioning

confidence: 99%

Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases

2014

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The ubiquitin proteasome system (UPS) is the primary proteolytic quality control system in cells and has an essential function in the nervous system. UPS dysfunction has been linked to neurodegenerative conditions, including Alzheimer's, Parkinson's and Huntington's diseases. The pathology of neurodegenerative diseases is characterized by the abnormal accumulation of insoluble protein aggregates or inclusion bodies within neurons. The failure or dysregulation of the UPS prevents the degradation of misfolded/aberrant proteins, leading to deficient synaptic function that eventually affects the nervous system. In this review, we discuss the UPS and its physiological roles in the nervous system, its influence on neuronal function, and how UPS dysfunction contributes to the development of neurodegenerative diseases.

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The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells

Cited by 45 publications

References 41 publications

Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation

Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases

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