VIB-VUB Center for Structural Biology, Pleinlaan 2, B-1050 Brussels, Belgium.
Department of Cell Biochemistry, University of Groningen, NL-9747 AG Groningen, The Netherlands.
Int J Mol Sci. 2019 Jan 3;20(1):147. doi: 10.3390/ijms20010147.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of genetically inherited Parkinson's Disease (PD). LRRK2 is a large, multi-domain protein belonging to the Roco protein family, a family of GTPases characterized by a central RocCOR (Ras of complex proteins/C-terminal of Roc) domain tandem. Despite the progress in characterizing the GTPase function of Roco proteins, there is still an ongoing debate concerning the working mechanism of Roco proteins in general, and LRRK2 in particular. This review consists of two parts. First, an overview is given of the wide evolutionary range of Roco proteins, leading to a variety of physiological functions. The second part focusses on the GTPase function of the RocCOR domain tandem central to the action of all Roco proteins, and progress in the understanding of its structure and biochemistry is discussed and reviewed. Finally, based on the recent work of our and other labs, a new working hypothesis for the mechanism of Roco proteins is proposed.
LRRK2（富含亮氨酸重复激酶 2）基因突变是遗传性帕金森病（PD）的常见原因。LRRK2 是一种大型多功能蛋白，属于 Roco 蛋白家族，该家族的 GTPase 以中央 RocCOR（Ras 相关蛋白/ Roc 羧基末端）结构域串联为特征。尽管在表征 Roco 蛋白的 GTPase 功能方面取得了进展，但对于 Roco 蛋白的一般工作机制，特别是 LRRK2 的工作机制，仍存在持续的争论。本综述由两部分组成。第一部分概述了 Roco 蛋白广泛的进化范围，导致了多种生理功能。第二部分重点介绍了所有 Roco 蛋白作用的核心 RocCOR 结构域串联的 GTPase 功能，并讨论和回顾了其结构和生物化学方面的进展。最后，基于我们和其他实验室的最新工作，提出了 Roco 蛋白作用机制的一个新的工作假设。
