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    Optimized PAR-2 RING dimerization mediates cooperative and selective membrane binding for robust cell polarity

    Bland, T. and Hirani, N. and Briggs, D. and Rossetto, R. and Ng, K. and McDonald, Neil Q. and Zwicker, D. and Goehring, N.W. (2024) Optimized PAR-2 RING dimerization mediates cooperative and selective membrane binding for robust cell polarity. Embo Journal 43 (15), pp. 3214-3239. ISSN 0261-4189.

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    Optimized dimerization of the PAR-2 RING domain drives cooperative and selective membrane recruitment for robust feedback-driven cell polarization - 2023.08.10.552581v1.full.pdf - Author's Accepted Manuscript
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    Abstract

    Cell polarity networks are defined by quantitative features of their constituent feedback circuits, which must be tuned to enable robust and stable polarization, while also ensuring that networks remain responsive to dynamically changing cellular states and/or spatial cues during development. Using the PAR polarity network as a model, we demonstrate that these features are enabled by the dimerization of the polarity protein PAR-2 via its N-terminal RING domain. Combining theory and experiment, we show that dimer affinity is optimized to achieve dynamic, selective, and cooperative binding of PAR-2 to the plasma membrane during polarization. Reducing dimerization compromises positive feedback and robustness of polarization, while enhanced dimerization renders the network less responsive due to kinetic trapping of PAR-2 on internal membranes and reduced sensitivity of PAR-2 to the anterior polarity kinase, aPKC/PKC-3. Thus, our data reveal a key role for a dynamically oligomeric RING domain in optimizing interaction affinities to support a robust and responsive cell polarity network and highlight how optimization of oligomerization kinetics can serve as a strategy for dynamic and cooperative intracellular targeting.

    Metadata

    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Neil Mcdonald
    Date Deposited: 06 Jun 2024 09:27
    Last Modified: 08 Sep 2024 19:22
    URI: https://eprints.bbk.ac.uk/id/eprint/53635

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