8R3X

Crystal structure of aPKC Iota kinase domain with LLGL2 peptide

Summary for 8R3X

• Entry DOI: 10.2210/pdb8r3x/pdb
• Descriptor: Protein kinase C iota type, LLGL scribble cell polarity complex component 2 (3 entities in total)
• Functional Keywords: kinase, polarity, kinase substrate complex., cytosolic protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 86938.15

Authors

Soriano, E.V.,Earl, C.P.,Briggs, D.C.,McDonald, N.Q. (deposition date: 2023-11-10, release date: 2024-11-20, Last modification date: 2025-04-23)

Primary citation

Earl, C.P.,Cobbaut, M.,Barros-Carvalho, A.,Ivanova, M.E.,Briggs, D.C.,Morais-de-Sa, E.,Parker, P.J.,McDonald, N.Q.
Capture, mutual inhibition and release mechanism for aPKC-Par6 and its multisite polarity substrate Lgl.
Nat.Struct.Mol.Biol., 32:729-739, 2025

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 aPKCι-Par6α bound to full-length Llgl1, captured through an aPKCι docking site and a Par6 contact. This complex traps a phospho-S663 Llgl1 intermediate bridging between aPKC and Par6, impeding phosphorylation progression. Thus, aPKCι is effectively inhibited by Llgl1 while Llgl1 is captured by aPKCι-Par6. Mutational disruption of the Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl-Par6 contact promotes complex dissociation and Lgl phosphorylation. We demonstrate a Par6-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.

PubMed: 39762628
DOI: 10.1038/s41594-024-01425-0

Experimental method

X-RAY DIFFRACTION (2.591 Å)