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bioRxiv · 10.1101/2024.11.22.624879

14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state

Martinez Fiesco, J. A.·Li, N.·Alvarez de la Cruz, A.·Metcalfe, R. D.·Beilina, A.·Cookson, M. R.·Zhang, P.
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Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a central player in cellular signaling and a significant contributor to Parkinsons disease (PD) pathogenesis. 14-3-3 proteins are essential regulators of LRRK2, modulating its activity. Here, we present the cryo- electron microscopy structure of the LRRK2:14-3-32 autoinhibitory complex, showing that a 14-3-3 dimer stabilizes an autoinhibited LRRK2 monomer by binding to key phosphorylation sites and the COR-A and COR-B subdomains within the Roc-COR GTPase domain of LRRK2. This interaction locks LRRK2 in an inactive conformation, restricting LRR domain mobility and preventing dimerization and oligomer formation. Our mutagenesis studies reveal that PD-associated mutations at the COR:14-3-3 interface and within the GTPase domain reduce 14-3-3 binding, diminishing its inhibitory effect on LRRK2. These findings provide a structural basis for understanding how LRRK2 likely remains dormant within cells, illuminate aspects of critical PD biomarkers, and suggest therapeutic strategies to enhance LRRK2-14-3-3 interactions to treat PD and related disorders.

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Martinez Fiesco, J. A., Li, N., Alvarez de la Cruz, A., Metcalfe, R. D., Beilina, A., Cookson, M. R., Zhang, P.. 2024-11-22. 14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state. https://doi.org/10.1101/2024.11.22.624879

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