Department of Neurology, Columbia University Medical Center, New York, New York, United States of America.
PLoS One. 2009 Dec 24;4(12):e8463. doi: 10.1371/journal.pone.0008463.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD). LRRK2 contains an "enzymatic core" composed of GTPase and kinase domains that is flanked by leucine-rich repeat (LRR) and WD40 protein-protein interaction domains. While kinase activity and GTP-binding have both been implicated in LRRK2 neurotoxicity, the potential role of other LRRK2 domains has not been as extensively explored.
We demonstrate that LRRK2 normally exists in a dimeric complex, and that removing the WD40 domain prevents complex formation and autophosphorylation. Moreover, loss of the WD40 domain completely blocks the neurotoxicity of multiple LRRK2 PD mutations.
These findings suggest that LRRK2 dimerization and autophosphorylation may be required for the neurotoxicity of LRRK2 PD mutations and highlight a potential role for the WD40 domain in the mechanism of LRRK2-mediated cell death.
富含亮氨酸重复激酶 2（LRRK2）的突变是帕金森病（PD）最常见的遗传原因。LRRK2 包含由 GTPase 和激酶结构域组成的“酶核心”，其两侧为富含亮氨酸重复（LRR）和 WD40 蛋白-蛋白相互作用结构域。虽然激酶活性和 GTP 结合都与 LRRK2 的神经毒性有关，但其他 LRRK2 结构域的潜在作用尚未得到广泛探索。
我们证明 LRRK2 通常以二聚体复合物的形式存在，并且去除 WD40 结构域会阻止复合物形成和自身磷酸化。此外，丧失 WD40 结构域完全阻止了多种 LRRK2 PD 突变的神经毒性。
这些发现表明 LRRK2 二聚化和自身磷酸化可能是 LRRK2 PD 突变神经毒性所必需的，并突出了 WD40 结构域在 LRRK2 介导的细胞死亡机制中的潜在作用。
