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TitleRAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 8434, Year 2024
Publish dateSep 29, 2024
AuthorsXingjian Li / Hanwen Zhu / Bik Tzu Huang / Xianting Li / Heesoo Kim / Haiyan Tan / Yuanxi Zhang / Insup Choi / Junmin Peng / Pingyi Xu / Ji Sun / Zhenyu Yue /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:39343966 / PubMed Central
MethodsEM (single particle)
Resolution4.0 - 4.1 Å
Structure data

43234

8vh4

EMDB-43234, PDB-8vh4:
Cryo-EM structure of Rab12-LRRK2 complex in the LRRK2 monomer state
Method: EM (single particle) / Resolution: 4.1 Å

43235

8vh5

EMDB-43235, PDB-8vh5:
Cryo-EM structure of Rab12-LRRK2 complex in the LRRK2 dimer state
Method: EM (single particle) / Resolution: 4.0 Å

Chemicals

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsHYDROLASE / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / Rab GTPases

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