9ci3 | pdb_00009ci3

Structure of the LRRK2/14-3-3 complex

spinqualitylabelsall models 9ci3, resolution 3.96Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ci3 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.96Å Ligands: GDP, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 1433G_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Publication Abstract from PubMed 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(2) 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(2) 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. 14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state.,Martinez Fiesco JA, Beilina A, Alvarez de la Cruz A, Li N, Metcalfe RD, Cookson MR, Zhang P Nat Commun. 2025 Aug 5;16(1):7226. doi: 10.1038/s41467-025-62337-1. PMID:40764514 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA