Li X, Wang QJ, Pan N, Lee S, Zhao Y, Chait BT, Yue Z.
Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease.
PLoS One. 2011;6(3):e17153.
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The manuscript by Zhenyu Yue’s group presents a comprehensive analysis of the interaction of LRRK2 with 14-3-3 proteins, and adds to a growing body of literature suggesting that 14-3-3 proteins regulate LRRK2 function. The first report by Nichols and colleagues demonstrated that LRRK2 binds a wide range of 14-3-3 proteins, and conveyed that many disease-linked mutations in LRRK2 reduce binding to 14-3-3 (Nichols et al., 2010). Yue’s manuscript (buttressed by the two manuscripts from Alessi and Nichols’s group that were published while Yue’s manuscript was in review supporting both the binding of 14-3-3 proteins to LRRK2 and the inhibition of binding by some mutations in LRRK2 (Nichols et al., 2010; Dzamko et al., 2010). It is important to note that the G2019S mutation, which is the most common disease-linked mutation, does not reduce binding to 14-3-3. Thus, interaction with 14-3-3 proteins are unlikely to represent mechanisms underlying the pathophysiology of LRRK2-mediated PD.
The 14-3-3 proteins specifically recognize phosphorylated proteins, and appear to be part of the mechanism that amplifies the effects of protein phosphorylation by modifying conformation, binding properties, or location. In the current manuscript, Yue’s team identifies a particular site on LRRK2, S935, whose phosphorylation is required for binding of 14-3-3 to LRRK2. They also generated an antibody that selectively identifies the S935 site on LRRK2 and demonstrate that it is constitutively phosphorylated. This antibody adds to a growing arsenal of antibodies available to study LRRK2 and should facilitate research greatly.
The role of 14-3-3 proteins in regulating LRRK2 function remains a mystery. The group examined whether 14-3-3 modulates LRRK2 dimerization, but did not find evidence of this. Nichols and colleagues found that the S935 site recognized by 14-3-3 modulates formation of LRRK2 inclusions because the S935A mutant stimulates formation of cytoplasmic inclusions. Whether this is due to 14-3-3 binding or some other mechanism remains unclear, but it provides suggestive evidence that this particular phosphorylation site regulates one physiologic action of LRRK2. Yue’s team proposes that 14-3-3 modulates the conformation of LRRK2, and that some of the disease-linked mutations in LRRK2 abrogate or reduce this binding. How this affects cellular physiology, though, remains unclear. Nevertheless, this work represents an important addition to the literature and describes a new reagent that will be of value in PD research.
Nichols RJ, Dzamko N, Morrice NA, Campbell DG, Deak M, Ordureau A, Macartney T, Tong Y, Shen J, Prescott AR, Alessi DR.
14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization.
Biochem J. 2010 Sep 15;430(3):393-404.
Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR, Nichols RJ.
Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization.
Biochem J. 2010 Sep 15;430(3):405-13.
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