Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places.

中文翻译：

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LRRK2 从结构到功能障碍的生物学：研究取得进展，但主题保持不变。

自从发现富含亮氨酸重复激酶 2 (LRRK2) 作为可能是帕金森病病因学核心的蛋白质以来，已经开展了大量工作来揭示其基本细胞功能。这一努力导致了 LRRK2 在一系列令人眼花缭乱的细胞生物学过程和途径中的意义，并可能在许多看似无关的医学状况中发挥作用。在这篇综述中，我们总结了 LRRK2 的基本生物化学和细胞功能的当前知识。涵盖的主题包括识别 LRRK2 激酶活性的磷酸化底物，尤其是 Rab 蛋白，以及通过二聚化和与膜结合，尤其是通过与 Rab29 的相互作用，了解 LRRK2 激酶活性激活的进展。我们还讨论了阐明复杂的 LRRK2 GTPase 活性的生化研究、LRRK2 在一系列可能具有细胞类型特异性的细胞信号通路中的作用的证据，以及将 LRRK2 与细胞器的细胞生物学联系起来的研究。后者包括 LRRK2 参与自噬、内吞作用和跨高尔基网络、内质网以及基于微管的关键细胞结构的过程。我们进一步提出了一种将 LRRK2 二聚化、GTPase 功能和膜募集与 Rab29 激活 LRRK2 激酶联系起来的机制。这些数据共同描绘了一个研究领域的图景，该领域在许多方面正以巨大的势头向前发展，但在其他方面并没有发生根本性的变化。已经取得了许多关键的进步，但它们往往似乎又回到了同一个地方。