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

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journal contribution
posted on 2024-08-06, 13:58 authored by Tom Bland, Nisha Hirani, David C Briggs, Riccardo Rossetto, KangBo Ng, Ian A Taylor, Neil Q McDonald, David Zwicker, Nathan W Goehring
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. Conversely, 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.

Funding

Crick (Grant ID: CC2119, Grant title: Goehring CC2119) Crick (Grant ID: CC2068, Grant title: McDonald CC2068) Crick (Grant ID: CC2029, Grant title: Taylor CC2029)

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