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 kcat (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 kcat (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.
| Original language | English |
|---|---|
| Pages (from-to) | 176-183 |
| Number of pages | 8 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 304 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Apr 25 2003 |
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All Science Journal Classification (ASJC) codes
- Biophysics
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants. / Nishikawa, Kaori; Li, Hang; Kawamura, Ryoichi; Osaka, Hitoshi; Wang, Yu Lai; Hara, Yoko; Hirokawa, Takatsugu; Manago, Yoshimasa; Amano, Taiju; Noda, Mami; Aoki, Shunsuke; Wada, Keiji.
In: Biochemical and Biophysical Research Communications, Vol. 304, No. 1, 25.04.2003, p. 176-183.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants
AU - Nishikawa, Kaori
AU - Li, Hang
AU - Kawamura, Ryoichi
AU - Osaka, Hitoshi
AU - Wang, Yu Lai
AU - Hara, Yoko
AU - Hirokawa, Takatsugu
AU - Manago, Yoshimasa
AU - Amano, Taiju
AU - Noda, Mami
AU - Aoki, Shunsuke
AU - Wada, Keiji
PY - 2003/4/25
Y1 - 2003/4/25
N2 - 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 kcat (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 kcat (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.
AB - 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 kcat (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 kcat (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.
UR - http://www.scopus.com/inward/record.url?scp=0037466510&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037466510&partnerID=8YFLogxK
U2 - 10.1016/S0006-291X(03)00555-2
DO - 10.1016/S0006-291X(03)00555-2
M3 - Article
C2 - 12705903
AN - SCOPUS:0037466510
VL - 304
SP - 176
EP - 183
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -