Presentation Information
[POS-04]Disordered vs. Structured Phosphorylation Modelings of Signal Transduction: AlphaFold and Signal Trade-offs
*Ryu Takayanagi1, Emiri Watanabe1, Ryosuke Iritani2, Kentaro Tomii3, Hafumi Nishi4, Shinya Kuroda1 (1. Department of Biological Sciences, Graduate School of Science, The University of Tokyo (Japan), 2. RIKEN Center for Interdisciplinary Theoretical and Mathematical Sciences (Japan), 3. Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST) (Japan), 4. Graduate School of Information Sciences, Tohoku University (Japan))
Keywords:
Protein Phosphorylation,Signal Transduction,AlphaFold,Signal Efficiency
Protein phosphorylation is a fundamental post-translational modification (PTM) essential for diverse cellular processes, including signal transduction. Many phosphorylation events occur in intrinsically disordered regions (IDRs) rather than in well-structured domains. Phosphorylation in IDRs provides enhanced flexibility and rapid reaction kinetics, albeit with lower substrate specificity. In contrast, phosphorylation within structured domains ensures high specificity through strong substrate affinity, but it typically proceeds with slower kinetics. This inherent trade-off raises essential questions about how these contrasting features contribute to effective signal transduction and why nature has evolutionarily favored such differential mechanisms.
In this study, we developed a mathematical model that integrates principles from information and control theory to evaluate the trade-offs between phosphorylation in IDRs versus structured domains for reaction speed, substrate specificity, and signaling efficiency. Using a representative insulin signaling network in which multiple kinases share conserved substrate linear motifs, we examined how the sharing of these motifs affects signal fidelity by modulating both robustness to noise and reaction speed. Structural insights from AlphaFold3 complex predictions are incorporated into our analysis to refine our understanding of how the spatial arrangement of kinase and adaptor protein interactions modulates phosphorylation dynamics. Our integrated approach may pave the way for clarifying the functional trade-offs underlying signal transduction and insights into how molecular mechanisms work together to optimize cellular communication.
In this study, we developed a mathematical model that integrates principles from information and control theory to evaluate the trade-offs between phosphorylation in IDRs versus structured domains for reaction speed, substrate specificity, and signaling efficiency. Using a representative insulin signaling network in which multiple kinases share conserved substrate linear motifs, we examined how the sharing of these motifs affects signal fidelity by modulating both robustness to noise and reaction speed. Structural insights from AlphaFold3 complex predictions are incorporated into our analysis to refine our understanding of how the spatial arrangement of kinase and adaptor protein interactions modulates phosphorylation dynamics. Our integrated approach may pave the way for clarifying the functional trade-offs underlying signal transduction and insights into how molecular mechanisms work together to optimize cellular communication.