9CI3

Structure of the LRRK2/14-3-3 complex

Summary for 9CI3

• Entry DOI: 10.2210/pdb9ci3/pdb
• EMDB information: 45609
• Descriptor: 14-3-3 protein gamma, Leucine-rich repeat serine/threonine-protein kinase 2, GUANOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: lrrk2, lrrk2 complex, lrrk2 14-3-3 complex, lrrk2 autoinhibited, transferase, transferase-signaling protein complex, transferase/signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 351969.02

Authors

Martinez Fiesco, J.A.,Zhang, P. (deposition date: 2024-07-02, release date: 2025-09-03)

Primary citation

Martinez Fiesco, J.A.,Beilina, A.,Alvarez de la Cruz, A.,Li, N.,Metcalfe, R.D.,Cookson, M.R.,Zhang, P.
14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state.
Nat Commun, 16:7226-7226, 2025

PubMed Abstract: Leucine-rich repeat kinase 2 (LRRK2) is an essential regulator in cellular signaling and a major contributor to Parkinson's disease (PD) pathogenesis. 14-3-3 proteins are critical modulators of LRRK2 activity, yet the structural basis of their interaction has remained unclear. Here, we present the cryo-electron microscopy structure of the LRRK2:14-3-3 autoinhibitory complex, revealing how a 14-3-3 dimer stabilizes an autoinhibited LRRK2 monomer through dual-site anchoring. The dimer engages both phosphorylated S910/S935 sites and the COR-A/B subdomains within the Roc-COR GTPase region. This spatial configuration constrains LRR domain mobility, reinforces the inactive conformation, and likely impedes LRRK2 dimerization and oligomer formation. Structure-guided mutagenesis studies show that PD-associated mutations at the COR:14-3-3 interface and within the GTPase domain weaken 14-3-3 binding and impair its inhibitory effect on LRRK2 kinase activity. Furthermore, we demonstrate that type I LRRK2 kinase inhibitor, which stabilizes the kinase domain in its active conformation, reduces 14-3-3 binding and promotes dephosphorylation at pS910 and pS935. Together, these findings provide a structural basis for understanding how LRRK2 is maintained in an inactive state, elucidate the mechanistic role of 14-3-3 in LRRK2 regulation, inform the interpretation of PD biomarkers, and suggest therapeutic strategies aimed at enhancing LRRK2-14-3-3 interactions to treat PD and related disorders.

PubMed: 40764514
DOI: 10.1038/s41467-025-62337-1

Experimental method

ELECTRON MICROSCOPY (3.96 Å)