Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.

中文翻译：

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富含亮氨酸的重复激酶

富含亮氨酸重复激酶 2 (LRRK2) 的激活突变是单基因帕金森病的最常见原因。 LRRK2 是一种大型多结构域蛋白激酶，可磷酸化 ∼65 种人类 Rab GTP 酶的特定子集，这些酶是分泌和内吞途径的主要调节因子。被 LRRK2 磷酸化后，Rab 失去结合同源效应蛋白和鸟嘌呤核苷酸交换因子的能力。此外，磷酸化的 Rab 不能与其同源异戊烯基结合修复蛋白（也称为鸟嘌呤核苷酸解离抑制剂）相互作用，因此它们被捕获在膜表面。相反，它们获得了结合磷酸化 Rab 特异性效应蛋白（例如 RILPL1）的能力，从而产生病理后果。 Rab 蛋白还通过控制 LRRK2 的激活和募集到膜上而在 LRRK2 上游发挥作用。 LRRK2 信号传导被磷蛋白磷酸酶 PPM1H 抵消，该酶选择性地使磷酸 Rab 蛋白去磷酸化。我们在此介绍我们目前对 LRRK2 及其相关旁系同源物 LRRK1 的结构、生化特性和细胞生物学的理解，并讨论这些信息如何指导 LRRK2 抑制剂的产生，从而为患者带来潜在利益。