Capture, mutual inhibition and release mechanism for aPKC-Par6 and its multi-site polarity substrate Lgl

Earl, C.P. and Cobbaut, M. and Barros-Carvalho, A. and Ivanova, M.E. and Briggs, D.C. and Morais-de-Sa, E. and Parker, P.J. and McDonald, Neil Q. (2025) Capture, mutual inhibition and release mechanism for aPKC-Par6 and its multi-site polarity substrate Lgl. Nature Structural & Molecular Biology , ISSN 1545-9993.

Abstract

The mutually antagonistic relationship between the aPKC-Par6 kinase and the substrate 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, paradoxically, aPKC-Par6 and Lgl forms a stable kinase substrate complex, with conflicting roles proposed for Par6. We report the structure of human aPKCι-Par6α bound to full-length Llgl1, captured through an aPKCi docking site and a Par6PDZ contact. This complex traps a phospho-S663 Llgl1 intermediate bridging between aPKC and Par6, impeding phosphorylation progression. Thus, aPKCι is effectively inhibited by Llgl1pS663 whilst Llgl1 is captured by aPKCι-Par6. Mutational disruption of Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl-Par6PDZ contact promotes complex dissociation and Lgl phosphorylation. We demonstrate a Par6PDZ-regulated substrate capture-and-release model requiring binding by Cdc42-GTP 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. Christopher P. Earl1,*, Mathias Cobbaut1,2,*, André Barros-Carvalho3,4, Marina E. Ivanova1,5, David C. Briggs1, Eurico Morais-de-Sá3,4, Peter J. Parker2,6 & Neil Q. McDonald1,7

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