Reevaluation of phosphorylation sites in the parkinson disease-associated leucine-rich repeat kinase 2

Xiaojie Li, Darren J. Moore, Yulan Xiong, Ted M Dawson, Valina Dawson

Research output: Contribution to journalArticle

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an important cause of late-onset, autosomal dominant familial Parkinson disease and contribute to sporadic Parkinson disease. LRRK2 is a large complex protein with multiple functional domains, including a Roc-GTPase, protein kinase, and multiple protein-protein interaction domains. Previous studies have suggested an important role for kinase activity in LRRK2-induced neuronal toxicity and inclusion body formation. Disease-associated mutations in LRRK2 also tend to increase kinase activity. Thus, enhanced kinase activity may therefore underlie LRRK2-linked disease. Similar to the closely related mixed-lineage kinases, LRRK2 can undergo autophosphorylation in vitro. Three putative autophosphorylation sites (Thr-2031, Ser-2032, and Thr-2035) have been identified within the activation segment of the LRRK2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of LRRK2. Sensitive phopho-specific antibodies to each of these three sites have been developed and validated by ELISA, dot-blot, and Western blot analysis. Using these antibodies, we have found that all three putative sites are phosphorylated in LRRK2, and Ser-2032 and Thr-2035 are the two important sites that regulate LRRK2 kinase activity.

Original languageEnglish (US)
Pages (from-to)29569-29576
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number38
DOIs
StatePublished - Sep 17 2010

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Phosphorylation
Leucine
Parkinson Disease
Phosphotransferases
Protein Interaction Domains and Motifs
Mutation
Antibodies
GTP Phosphohydrolases
Inclusion Bodies

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Reevaluation of phosphorylation sites in the parkinson disease-associated leucine-rich repeat kinase 2. / Li, Xiaojie; Moore, Darren J.; Xiong, Yulan; Dawson, Ted M; Dawson, Valina.

In: Journal of Biological Chemistry, Vol. 285, No. 38, 17.09.2010, p. 29569-29576.

Research output: Contribution to journalArticle

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