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

Kaori Nishikawa, Hang Li, Ryoichi Kawamura, Hitoshi Osaka, Yu Lai Wang, Yoko Hara, Takatsugu Hirokawa, Yoshimasa Manago, Taiju Amano, Mami Noda, Shunsuke Aoki, Keiji Wada

Research output: Contribution to journalArticle

127 Citations (Scopus)

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 languageEnglish
Pages (from-to)176-183
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume304
Issue number1
DOIs
Publication statusPublished - Apr 25 2003

Fingerprint

Parkinsonian Disorders
Hydrolases
Ubiquitin
Parkinson Disease
Substitution reactions
Oxidative stress
Cell death
Circular Dichroism
Polymorphism
Neurons
Recycling
Oxidative Stress
Cell Death
Oxidation
Mutation

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 journalArticle

Nishikawa, K, Li, H, Kawamura, R, Osaka, H, Wang, YL, Hara, Y, Hirokawa, T, Manago, Y, Amano, T, Noda, M, Aoki, S & Wada, K 2003, 'Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants', Biochemical and Biophysical Research Communications, vol. 304, no. 1, pp. 176-183. https://doi.org/10.1016/S0006-291X(03)00555-2
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. / Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants. In: Biochemical and Biophysical Research Communications. 2003 ; Vol. 304, No. 1. pp. 176-183.
@article{1002cd6e68804f79bee420a19c7c2be9,
title = "Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants",
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.",
author = "Kaori Nishikawa and Hang Li and Ryoichi Kawamura and Hitoshi Osaka and Wang, {Yu Lai} and Yoko Hara and Takatsugu Hirokawa and Yoshimasa Manago and Taiju Amano and Mami Noda and Shunsuke Aoki and Keiji Wada",
year = "2003",
month = "4",
day = "25",
doi = "10.1016/S0006-291X(03)00555-2",
language = "English",
volume = "304",
pages = "176--183",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

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 -