aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization

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

doi:10.1016/j.devcel.2016.07.018

aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization

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

Randall Centre of Cell & Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

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Abstract

Summary 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.

Original language	English
Pages (from-to)	384-398
Number of pages	15
Journal	Developmental Cell
Volume	38
Issue number	4
Early online date	22 Aug 2016
DOIs	https://doi.org/10.1016/j.devcel.2016.07.018
Publication status	Published - 22 Aug 2016

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aPKC Inhibition by Par3 CR3_SORIANO_Accepted24July2016_GOLD VoRFinal published version, 5.14 MBLicence: CC BY

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Soriano, EV., Ivanova, ME., Fletcher, G., Riou, P., Knowles, PP., Barnouin, K., Purkiss, A., Kostelecky, B., Saiu, P., Linch, M., Elbediwy, A., Kjær, S., O’Reilly, N., Snijders, AP., Parker, PJ., Thompson, BJ., & McDonald, NQ. (2016). aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization. Developmental Cell, 38(4), 384-398. https://doi.org/10.1016/j.devcel.2016.07.018

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title = "aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization",

abstract = "Summary 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.",

author = "Erika V. Soriano and Marina E. Ivanova and Georgina Fletcher and Philippe Riou and Philip P. Knowles and Karin Barnouin and Andrew Purkiss and Brenda Kostelecky and Peter Saiu and Mark Linch and Ahmed Elbediwy and Svend Kj{\ae}r and Nicola O{\textquoteright}Reilly and Ambrosius P. Snijders and Peter J. Parker and Barry J. Thompson and Neil Q. McDonald",

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doi = "10.1016/j.devcel.2016.07.018",

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Soriano, EV, Ivanova, ME, Fletcher, G, Riou, P, Knowles, PP, Barnouin, K, Purkiss, A, Kostelecky, B, Saiu, P, Linch, M, Elbediwy, A, Kjær, S, O’Reilly, N, Snijders, AP, Parker, PJ, Thompson, BJ & McDonald, NQ 2016, 'aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization', Developmental Cell, vol. 38, no. 4, pp. 384-398. https://doi.org/10.1016/j.devcel.2016.07.018

TY - JOUR

T1 - aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization

AU - Soriano, Erika V.

AU - Ivanova, Marina E.

AU - Fletcher, Georgina

AU - Riou, Philippe

AU - Knowles, Philip P.

AU - Barnouin, Karin

AU - Purkiss, Andrew

AU - Kostelecky, Brenda

AU - Saiu, Peter

AU - Linch, Mark

AU - Elbediwy, Ahmed

AU - Kjær, Svend

AU - O’Reilly, Nicola

AU - Snijders, Ambrosius P.

AU - Parker, Peter J.

AU - Thompson, Barry J.

AU - McDonald, Neil Q.

PY - 2016/8/22

Y1 - 2016/8/22

N2 - Summary 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.

AB - Summary 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.

U2 - 10.1016/j.devcel.2016.07.018

DO - 10.1016/j.devcel.2016.07.018

M3 - Article

SN - 1534-5807

VL - 38

SP - 384

EP - 398

JO - Developmental Cell

JF - Developmental Cell

IS - 4

ER -

aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization

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