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Differential effects of familial parkinson mutations in LRRK2 revealed by a systematic analysis of autophosphorylation.
- Source :
-
Biochemistry [Biochemistry] 2013 Sep 03; Vol. 52 (35), pp. 6052-62. Date of Electronic Publication: 2013 Aug 23. - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Chromatography, Thin Layer
HEK293 Cells
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Peptide Mapping
Phosphopeptides chemistry
Phosphorylation
Protein Serine-Threonine Kinases chemistry
Protein Serine-Threonine Kinases metabolism
Threonine chemistry
Mutation
Parkinson Disease genetics
Protein Serine-Threonine Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 52
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23924436
- Full Text :
- https://doi.org/10.1021/bi400596m