14-3-3 proteins are promising LRRK2 interactors.
14-3-3 proteins are promising LRRK2 interactors.
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DOI：
10.1042/bj20101200
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
I. Rudenko;M. Cookson
中科院分区：
文献类型：
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作者：
I. Rudenko;M. Cookson
LRRK2（富亮氨酸重复激酶2）突变是家族性PD（帕金森病）的最常见原因。导致PD的突变存在于LRRK2的GTPase或激酶结构域或称为COR [ROC（复杂蛋白的Ras）的c -末端]结构域的中间序列中。除了这两个催化结构域外，LRRK2还具有几个蛋白-蛋白相互作用结构域，但它们的功能以及与它们相互作用的蛋白质知之甚少。在这一期的《生化杂志》上，Nichols等人研究了LRRK2 n端区域与14-3-3蛋白的相互作用，14-3-3蛋白是一种经常与细胞信号通路成分磷酸化区域结合的调节蛋白。Nichols等人使用多种技术组合，确定了两个残基（Ser910和Ser935）对14-3-3结合起关键作用。LRRK2与14-3-3蛋白的相互作用可以阻止Ser910/Ser935的去磷酸化，并稳定LRRK2的结构，可能是通过影响LRRK2的二聚化。与14-3-3相互作用的能力与细胞内LRRK2分布模式相关。总的来说，这些新结果确定了这种复杂蛋白的潜在重要调节机制，并可能为PD的治疗机会提供方法。
Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common cause of familial PD (Parkinson's disease). Mutations that cause PD are found in either the GTPase or kinase domains of LRRK2 or an intervening sequence called the COR [C-terminus of ROC (Ras of complex proteins)] domain. As well as the two catalytic domains, LRRK2 possesses several protein-protein interaction domains, but their function and the proteins with which they interact are poorly understood. In this issue of the Biochemical Journal, Nichols et al. study the interaction of the N-terminal region of LRRK2 with 14-3-3 proteins, regulatory proteins that often bind to phosphorylated regions of components of cell signalling pathways. Using a combination of techniques, Nichols et al. have identified two residues (Ser910 and Ser935) that are critically responsible for 14-3-3 binding. The interaction of LRRK2 with 14-3-3 proteins can prevent dephosphorylation of Ser910/Ser935 and stabilize LRRK2 structure, perhaps by influencing the dimerization of LRRK2. The ability to interact with 14-3-3 correlates with the pattern of intracellular LRRK2 distribution. Collectively, these new results identify a potentially important regulatory mechanism of this complex protein and might provide ways to think about therapeutic opportunities for PD.