8VH4

Cryo-EM structure of Rab12-LRRK2 complex in the LRRK2 monomer state

Summary for 8VH4

• Entry DOI: 10.2210/pdb8vh4/pdb
• EMDB information: 43234
• Descriptor: Leucine-rich repeat serine/threonine-protein kinase 2, Ras-related protein Rab-12, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: cryo-em, parkinson's disease, kinase, lrrk2, rab gtpases, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 308130.92

Authors

Zhu, H.,Sun, J. (deposition date: 2023-12-30, release date: 2024-10-09)

Primary citation

Li, X.,Zhu, H.,Huang, B.T.,Li, X.,Kim, H.,Tan, H.,Zhang, Y.,Choi, I.,Peng, J.,Xu, P.,Sun, J.,Yue, Z.
RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes.
Nat Commun, 15:8434-8434, 2024

PubMed Abstract: The leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and their phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the LRRK2-regulated RAB GTPase in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brain 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 RILPL1, while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 activity. Furthermore, the ciliary and centrosome defects caused by the PD-linked LRRK2-G2019S mutation are prevented by Rab12 deletion in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.

PubMed: 39343966
DOI: 10.1038/s41467-024-52723-6

Experimental method

ELECTRON MICROSCOPY (4.1 Å)