SUN LAB @ NUS
LRRK2 Signaling
Parkinson's Disease (PD) is the second most common neurodegenerative disease. The prevalence of PD is about 1% at age 60 and 4% at age 80, affecting 8.5 million population worldwide in 2019. PD is thought to arise from complex interactions between genetic and environmental factors. Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in both familial and sporadic PD. LRRK2, a 286-kDa multidomain kinase, regulates critical cellular processes at membranous organelles, such as ciliogenesis, vesicle trafficking and mitochondrial integrity. Mutational LRRK2 also forms microtubule-based pathogenic filaments. As a valuable PD target, understanding the molecular basis of LRRK2 signaling will provide novel opportunities for PD treatment. My lab aims to elucidate the working mechanism of LRRK2, mainly focusing on two fundamental questions: 1) how do LRRK2 mutations lead to PD? 2) how can we target LRRK2 for treating PD?
The first high-resolution structure of full-length human LRRK2
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. We determined the first high-resolution structures of full-length human LRRK2, and highlights of this work include:
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the architecture of the full-length human LRRK2
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the structure of LRRK2 reveals disease hotspots and key scaffolding elements
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the LRRK2 kinase domain is captured in an inactive state, also adopted by the LRRK2-G2019S disease mutation
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structural analysis of the LRRK2 dimer
How is LRRK2 recruited and activated by membrane-anchored RAB29?
Based on our work on inactive LRRK2 structure, we then ask how LRRK2 is activated. RAB29, whose coding gene is located in the PARK16 locus, could recruit LRRK2 to the trans-Golgi membrane and boost LRRK2 kinase activity. Combining structural biology and biochemical approaches, we revealed
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the basis of Rab29-dependent membrane recruitment of LRRK2
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structures of LRRK2 in three different oligomerization states, including an unexpected tetrameric form of LRRK2
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the conformational changes upon LRRK2 activation
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a unique molecular paradigm of a kinase modulation mechanism based on non-symmetric tetramerization and spatial regulation
- Zhu H, Tonelli F, Turk M, Prescott A, Alessi D and Sun J. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. Science. 382: 1404-1411, 2023
Pharmacology studies of LRRK2 inhibition by type I and type II inhibitors
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 structural determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. We reported
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near-atomic-resolution structures of LRRK2 with type I (DNL201, LRRK2-IN-1, and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors;
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the structural basis of LRRK2 inhibition;
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conformational plasticity of the kinase domain with molecular dynamics (MD) simulations.
Our study provides atomic details of LRRK2–inhibitor interactions and a framework for understanding LRRK2 activation and rational drug design.
- Zhu H, Hixson P, Ma W** and Sun J**. Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. Cell Discovery, 10:10, 2024