Here, we developed a quantitative biophysical model to describe the coupled equilibria of Orf9b dimerization and Tom70 binding, revealing how lipid binding tunes the system.
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CJ measured key rate constants that constrained a model to show how lipid binding shifts Orf9b’s equilibrium towards the homodimer, preventing Tom70 interaction. The lipid-free form comes to equilibrium in seconds, whereas the lipid-bound form takes hours-days!
These results suggest that stabilizing Orf9b’s (lipid-bound) dimeric state could be a future therapeutic target. Disrupting lipid interactions might bias Orf9b towards a form that can’t bind Tom70, restoring immune activation.
We’re excited to push this work forward with CJ's next two papers. But in the meantime, we'd love to receive feedback from the community. Please reach out!
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https://grabelab.org/software
https://www.biorxiv.org/content/10.1101/2025.02.16.638509v1