纤毛形成
中心体
细胞生物学
平衡
小学(天文学)
LRRK2
纤毛
化学
生物
细胞凋亡
生物化学
物理
基因
细胞周期
天文
突变
作者
Jia Li,Hanwen Zhu,Bo Huang,Xianting Li,Hee‐Soo Kim,Haiyan Tan,Yuanxi Zhang,Insup Choi,Junmin Peng,Pingyi Xu,Ji Su Sun,Zhenyu Yue
标识
DOI:10.1101/2024.07.17.603999
摘要
Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and the phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the specific RAB GTPase targeted by LRRK2 signaling in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brains through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting Rab interacting lysosomal protein like 1 (RILPL1), while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 kinase activity. Furthermore, the ciliary deficits and centrosome alteration caused by the PD-linked LRRK2-G2019S mutation are prevented by the deletion of
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