| http://purl.uniprot.org/citations/21390248 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/21390248 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundRecent studies show that mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the cause of the most common inherited and some sporadic forms of Parkinson's disease (PD). The molecular mechanism underlying the pathogenic role of LRRK2 mutations in PD remains unknown.Methodology/principal findingsUsing affinity purification and mass spectrometric analysis, we investigated phosphorylation sites and binding proteins of LRRK2 purified from mouse brain. We identified multiple phosphorylation sites at N-terminus of LRRK2 including S910, S912, S935 and S973. Focusing on the high stoichiometry S935 phosphorylation site, we developed an anti-pS935 specific antibody and showed that LRRK2 is constitutively phosphorylated at S935 in various tissues (including brain) and at different ages in mice. We find that 14-3-3 proteins (especially isoforms γ and η) bind LRRK2 and this binding depends on phosphorylation of S935. The binding of 14-3-3, with little effect on dimer formation of LRRK2, confers protection of the phosphorylation status of S935. Furthermore, we show that protein kinase A (PKA), but not LRRK2 kinase itself, can cause the phosphorylation of LRRK2 at S935 in vitro and in cell culture, suggesting that PKA is a potential upstream kinase that regulates LRRK2 function. Finally, our study indicates that the common PD-related mutations of LRRK2, R1441G, Y1699C and G2019S, decrease homeostatic phosphorylation levels of S935 and impair 14-3-3 binding of LRRK2.Conclusions/significanceLRRK2 is extensively phosphorylated in vivo, and the phosphorylation of specific sites (e.g. S935) determines 14-3-3 binding of LRRK2. We propose that 14-3-3 is an important regulator of LRRK2-mediated cellular functions. Our study suggests that PKA, a cAMP-dependent kinase involved in regulating dopamine physiology, is a potential upstream kinase that phosphorylates LRRK2 at S935. Furthermore, the reduction of phosphorylation/14-3-3 binding of LRRK2 due to the common familial PD-related mutations provides novel insight into the pathogenic mechanism of LRRK2-linked PD."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.org/dc/terms/identifier | "doi:10.1371/journal.pone.0017153"xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/author | "Chait B.T."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/author | "Lee S."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/author | "Li X."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/author | "Zhao Y."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/author | "Pan N."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/author | "Yue Z."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/author | "Wang Q.J."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/date | "2011"xsd:gYear |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/name | "PLoS One"xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/pages | "e17153"xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/title | "Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease."xsd:string |
| http://purl.uniprot.org/citations/21390248 | http://purl.uniprot.org/core/volume | "6"xsd:string |
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