8R3Y
Cryo EM structure of a stable LGL/aPKC Iota/Par-6 complex
Summary for 8R3Y
| Entry DOI | 10.2210/pdb8r3y/pdb |
| EMDB information | 18877 |
| Descriptor | Protein kinase C iota type, Lethal(2) giant larvae protein homolog 1, Partitioning defective 6 homolog alpha, ... (4 entities in total) |
| Functional Keywords | kinase, polarity, kinase substrate complex., cytosolic protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 152398.52 |
| Authors | 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 Cited by 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: 39762628DOI: 10.1038/s41594-024-01425-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.68 Å) |
Structure validation
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