研究人员表示，LRRK2编码富亮氨酸重复激酶2（LRRK2），其功能增益突变是晚发性帕金森病最常见的遗传病因。LRRK2被招募到膜细胞器，并被PARK16基因座编码的Rab鸟苷三磷酸酶Rab29激活。
研究人员展示了三种低聚物状态下Rab29-LRRK2复合物的冷冻电镜结构，并提供了LRRK2招募和激活过程中的关键快照。Rab29诱导了LRRK2意外的四聚体组装，由两个具有激酶活性的中心原聚体和两个不具有激酶活性的外围原聚体组成。中心原聚体类似于I型激酶抑制剂DNL201所捕获的活性样状态，该化合物已进行了一期临床试验。这项研究揭示了LRRK2空间调控的结构机制，并为帕金森病治疗的LRRK2抑制剂设计提供了启示。
附：英文原文
Title: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2
Author: Hanwen Zhu, Francesca Tonelli, Martin Turk, Alan Prescott, Dario R. Alessi, Ji Sun
Issue&Volume: 2023-12-22
Abstract: Gain-of-function mutations in LRRK2, which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson’s disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the PARK16 locus. We present cryo–electron microscopy structures of Rab29–LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson’s disease treatment.
DOI: adi9926
Source: https://www.science.org/doi/10.1126/science.adi9926