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Norway

PMID:38907033  

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

Tom Bland | Nisha Hirani | David C Briggs | Riccardo Rossetto | KangBo Ng | Ian A Taylor | Neil Q McDonald | David Zwicker | Nathan W Goehring
The EMBO journal | 2024

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.

Pubmed ID: 38907033

Associated grants

  • Agency: ODCDC CDC HHS, United States
    Id: P40 OD010440
  • Agency: NIH HHS, United States
    Id: P40 OD010440
  • Agency: Wellcome Trust, United Kingdom
    Id: CC2119
  • Agency: Arthritis Research UK, United Kingdom
    Id: CC2119
  • Agency: Wellcome Trust, United Kingdom
    Id: CC2029
  • Agency: Arthritis Research UK, United Kingdom
    Id: CC2029
  • Agency: Wellcome Trust, United Kingdom
  • Agency: EC | European Research Council (ERC),
    Id: EmulSim,101044662
  • Agency: Wellcome Trust, United Kingdom
    Id: CC2068
  • Agency: Arthritis Research UK, United Kingdom
    Id: CC2068

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