期刊
BIOCHEMISTRY
卷 52, 期 35, 页码 6052-6062出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi400596m
关键词
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资金
- Japan Society for the Promotion of Science [22790058, 24790068]
- Ministry of Education, Culture, Sports, Science and Technology [17025009]
- Japan Science and Technology Agency (Core Research for Evolutional Science and Technology (CREST)
- Elan Pharmaceuticals (Innovation Program)
- Grants-in-Aid for Scientific Research [22790058, 24790068, 17025009] Funding Source: KAKEN
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified in pedigrees of autosomal-dominant familial Parkinson's disease (PARK8). It has been shown that the kinase activity of LRRK2 is required for its neuronal toxicity, although how familial Parkinson mutations affect the function of LRRK2 has not been well characterized. In the present study, we systematically characterized the autophosphorylation of LRRK2 by phosphopeptide mapping and identified Thr1348, Thr1349, and Thr1357 as the major autophosphorylation sites. We found that the autophosphorylation at Thr1357 is downregulated by the Y1699C mutation, possibly through a conformational alteration of the ROC domain. We also found that I2020T mutant LRRK2 undergoes excessive autophosphorylation in cell lysates in vitro at a low concentration of ATP. These results highlight the differential effects of familial mutations in LRRK2 on its conformation and enzymatic properties.
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