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Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants
- Source :
-
Biochemical & Biophysical Research Communications . Apr2003, Vol. 304 Issue 1, p176. 8p. - Publication Year :
- 2003
-
Abstract
- Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a neuron-specific ubiquitin recycling enzyme. A mutation at residue 93 and polymorphism at residue 18 within human UCH-L1 are linked to familial Parkinson’s disease and a decreased Parkinson’s disease risk, respectively. Thus, we constructed recombinant human UCH-L1 variants and examined their structure (using circular dichroism) and hydrolase activities. We confirmed that an I93M substitution results in a decrease in <f>kcat</f> (45.6%) coincident with an alteration in α-helical content. These changes may contribute to the pathogenesis of Parkinson’s disease. In contrast, an S18Y substitution results in an increase in <f>kcat</f> (112.6%) without altering the circular dichroistic spectrum. These data suggest that UCH-L1 hydrolase activity may be inversely correlated with Parkinson’s disease risk and that the hydrolase activity is protective against the disease. Furthermore, we found that oxidation of UCH-L1 by 4-hydroxynonenal, a candidate for endogenous mediator of oxidative stress-induced neuronal cell death, results in a loss of hydrolase activity. Taken together, these results suggest that further studies of altered UCH-L1 hydrolase function may provide new insights into a possible common pathogenic mechanism between familial and sporadic Parkinson’s disease. [Copyright &y& Elsevier]
- Subjects :
- *HYDROLASES
*UBIQUITIN
Subjects
Details
- Language :
- English
- ISSN :
- 0006291X
- Volume :
- 304
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Biochemical & Biophysical Research Communications
- Publication Type :
- Academic Journal
- Accession number :
- 9495958
- Full Text :
- https://doi.org/10.1016/S0006-291X(03)00555-2