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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. LRRK2 variants are linked to Parkinson's disease. Here, the authors solve the Cryo-EM structure of LRRK2 complexed to RAB12 and demonstrate that their interaction regulates cilia formation in astrocytes. [ABSTRACT FROM AUTHOR]

LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2–inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2–inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2–inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1038/s41421-023-00639-8.Correction to: Cell Discoveryhttps://doi.org/10.1038/s41421-023-00639-8 published online 23 January 2024As per Mansoore Esmaili's request, we would like to remove "M. Esmaili for help with kinase inhibition assay" from the Acknowledgements section. We apologize for the inconvenience.By Hanwen Zhu; Patricia Hixson; Wen Ma and Ji SunReported by Author; Author; Author; Author [Extracted from the article]

Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 regulates critical cellular processes at membranous organelles and forms microtubule-based pathogenic filaments, yet the molecular basis underlying these biological roles of LRRK2 remains largely enigmatic. Here, we determined high-resolution structures of full-length human LRRK2, revealing its architecture and key interdomain scaffolding elements for rationalizing disease-causing mutations. The kinase domain of LRRK2 is captured in an inactive state, a conformation also adopted by the most common PD-associated mutation, LRRK2G2019S. This conformation serves as a framework for structure-guided design of conformational specific inhibitors. We further determined the structure of COR-mediated LRRK2 dimers and found that single-point mutations at the dimer interface abolished pathogenic filamentation in cells. Overall, our study provides mechanistic insights into physiological and pathological roles of LRRK2 and establishes a structural template for future therapeutic intervention in PD. [Display omitted] • The architecture of the full-length human LRRK2 • The structure of LRRK2 reveals disease hotspots and key scaffolding elements • The LRRK2 kinase domain is captured in an inactive state also adopted by LRRK2G2019S • Structural analysis of the LRRK2 dimer High-resolution structure of full-length human LRRK2 captured in an inactive state provides view into the physiological and pathological roles of a commonly disrupted enzyme in familial and sporadic Parkinson's disease. [ABSTRACT FROM AUTHOR]