Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation
- Salk Institute for Biological Studies, United States
- Yale University, United States
Abstract
RAF kinase inhibitors can, under certain conditions, increase RAF kinase signaling. This process, which is commonly referred to as 'paradoxical activation' (PA), is incompletely understood. We use mathematical and computational modeling to investigate PA, and we derive rigorous analytical expressions that illuminate the underlying mechanism of this complex phenomenon. We find that conformational autoinhibition modulation by a RAF inhibitor could be sufficient to create PA. We find that experimental RAF-inhibitor drug dose response data that characterize PA across different types of RAF inhibitors are best explained by a model that includes RAF-inhibitor modulation of three properties: conformational autoinhibition, dimer affinity, and drug binding within the dimer (i.e., negative cooperativity). Overall, this work establishes conformational autoinhibition as a robust mechanism for RAF-inhibitor driven PA based solely on equilibrium dynamics of canonical interactions that comprise RAF signaling and inhibition.
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All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials. All materials are available upon request from the corresponding author.
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Funding
National Institutes of Health (K22CA216318)
- Edward Stites
National Institutes of Health (DP2AT011327)
- Edward Stites
Melanoma Research Alliance (Young Investigator Award)
- Edward Stites
Joe W. and Dorothy Dorsett Brown Foundation (N/A)
- Edward Stites
Salk Institute for Biological Studies
- Gaurav Mendiratta
Conrad Prebys Foundation (N/A)
- Edward Stites
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Mendiratta & Stites
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation
eLife 12:e82739.
https://doi.org/10.7554/eLife.82739
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