Alterations of structure and hydrolase activity of Parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants

作者：Nishikawa K; Li H; Kawamura R; Osaka H; Wang YL; Hara Y; Hirokawa T; Manago Y; Amano T; Noda M; Aoki S; Wada K^*

来源：Biochemical and Biophysical Research Communications, 2003, 304(1): 176-183.

DOI：10.1016/S0006-291X(03)00555-2

• ubiquitin
• proteasome
• UCH-L1
• Parkinsonism
• oxidative stress
• 4-hydroxynonenal

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 193M substitution results in a decrease in kat (45.6%) coincident with an alteration in alpha-helical content. These changes may contribute to the pathogenesis of Parkinson's disease. In contrast, an S18Y substitution results in an increase in k(cat) (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.

• 出版日期2003-4-25