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PNAS:研究发现帕金森氏病关键酶LRRK2的分子开关

来源:生物谷 2014-01-24 21:44

2014年1月24日讯 /生物谷BIOON/--近日,Kassel大学科学家发现控制LRRK2活性的一种机制,这开辟了药物来对抗疾病的新途径。在帕金森病中,酶LRRK2起着核心作用。

阿尔茨海默氏症,帕金森氏病是最经常发生的神经变性疾病。据估计,世界各地大约有700万人患有此病。这些疾病部分是有特异性基因突变引起的。

这些所谓的家族性帕金森氏突变在不同的族群中频率是不同的,某些突变在意大利和西班牙是特别普遍的。一个名为LRRK2蛋白的突变被看作是遗传帕金森病的最常见原因。

来自Kassel大学的一个研究小组现在已经发现了控制这种蛋白质活性的“分子开关”。新的研究结果可以证明调节这种蛋白质的活性可用来开发新的药物,从而治疗遗传性帕金森氏病。(生物谷Bioon.com)


 

Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3

Kathrin Mudaa, Daniela Bertinettia, Frank Gesellchenb, Jennifer Sarah Hermanna, Felix von Zweydorfc, Arie Geerlofd, Anette Jacobe, Marius Ueffing, Christian Johannes Gloecknerc, Friedrich W. Herberga

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain protein implicated in Parkinson disease (PD); however, the molecular mechanism and mode of action of this protein remain elusive. cAMP-dependent protein kinase (PKA), along with other kinases, has been suggested to be an upstream kinase regulating LRRK2 function. Using MS, we detected several sites phosphorylated by PKA, including phosphorylation sites within the Ras of complex proteins (ROC) GTPase domain as well as some previously described sites (S910 and S935). We systematically mapped those sites within LRRK2 and investigated their functional consequences. S1444 in the ROC domain was confirmed as a target for PKA phosphorylation using ROC single-domain constructs and through site-directed mutagenesis. Phosphorylation at S1444 is strikingly reduced in the major PD-related LRRK2 mutations R1441C/G/H, which are part of a consensus PKA recognition site (1441RASpS1444). Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site. Experiments of direct binding to the three 14-3-3 isotypes gamma, theta, and zeta with phosphopeptides encompassing pS910, pS935, or pS1444 demonstrated the highest affinities to phospho-S1444. Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro. Moreover, substitution of S1444 by alanine or by introducing the mutations R1441C/G/H, abrogating PKA phosphorylation and 14-3-3 binding, resulted in increased LRRK2 kinase activity. In conclusion, these data clearly demonstrate that LRRK2 kinase activity is modulated by PKA-mediated binding of 14-3-3 to S1444 and suggest that 14-3-3 interaction with LRRK2 is hampered in R1441C/G/H-mediated PD pathogenesis.

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