Download MendeleyCapture, mutual inhibition and release mechanism for aPKC-Par6 and its multisite polarity substrate Lgl.
Earl, C.P., Cobbaut, M., Barros-Carvalho, A., Ivanova, M.E., Briggs, D.C., Morais-de-Sa, E., Parker, P.J., McDonald, N.Q.(2025) Nat Struct Mol Biol
- PubMed: 39762628
- DOI: https://doi.org/10.1038/s41594-024-01425-0
- Primary Citation of Related Structures:
8R3X, 8R3Y - PubMed Abstract:
The mutually antagonistic relationship of atypical protein kinase C (aPKC) and partitioning-defective protein 6 (Par6) with the substrate lethal (2) giant larvae (Lgl) is essential for regulating polarity across many cell types. Although aPKC-Par6 phosphorylates Lgl at three serine sites to exclude it from the apical domain, aPKC-Par6 and Lgl paradoxically form a stable kinase-substrate complex, with conflicting roles proposed for Par6. We report the structure of human aPKC¦É-Par6¦Į bound to full-length Llgl1, captured through an aPKC¦É docking site and a Par6 PDZ contact. This complex traps a phospho-S663 Llgl1 intermediate bridging between aPKC and Par6, impeding phosphorylation progression. Thus, aPKC¦É is effectively inhibited by Llgl1 pS663 while Llgl1 is captured by aPKC¦É-Par6. Mutational disruption of the Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl-Par6 PDZ contact promotes complex dissociation and Lgl phosphorylation. We demonstrate a Par6 PDZ -regulated substrate capture-and-release model requiring binding by active Cdc42 and the apical partner Crumbs to drive complex disassembly. Our results suggest a mechanism for mutual regulation and spatial control of aPKC-Par6 and Lgl activities.
Organizational Affiliation:
Signalling and Structural Biology Laboratory, Francis Crick Institute, London, UK.
