The Francis Crick Institute
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aPKC inhibition by Par3 CR3 flanking regions controls substrate access and underpins apical-junctional polarization

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journal contribution
posted on 2020-10-02, 14:08 authored by Erika V Soriano, Marina E Ivanova, Georgina Fletcher, Philippe Riou, Philip P Knowles, Karin Barnouin, Andrew Purkiss, Brenda Kostelecky, Peter Saiu, Mark Linch, Ahmed Elbediwy, Svend Kjær, Nicola O'Reilly, Ambrosius P Snijders, Peter J Parker, Barry J Thompson, Neil Q McDonald
Atypical protein kinase C (aPKC) is a key apical-basal polarity determinant and Par complex component. It is recruited by Par3/Baz (Bazooka in Drosophila) into epithelial apical domains through high-affinity interaction. Paradoxically, aPKC also phosphorylates Par3/Baz, provoking its relocalization to adherens junctions (AJs). We show that Par3 conserved region 3 (CR3) forms a tight inhibitory complex with a primed aPKC kinase domain, blocking substrate access. A CR3 motif flanking its PKC consensus site disrupts the aPKC kinase N lobe, separating P-loop/αB/αC contacts. A second CR3 motif provides a high-affinity anchor. Mutation of either motif switches CR3 to an efficient in vitro substrate by exposing its phospho-acceptor site. In vivo, mutation of either CR3 motif alters Par3/Baz localization from apical to AJs. Our results reveal how Par3/Baz CR3 can antagonize aPKC in stable apical Par complexes and suggests that modulation of CR3 inhibitory arms or opposing aPKC pockets would perturb the interaction, promoting Par3/Baz phosphorylation.