Kinetic modelling reveals the presence of multistability in normal and stressful conditions in translational initiation mechanism
Guturu L. Harika, Krishnamachari Sriram
TL;DR
This paper uses mathematical modeling to show how protein synthesis initiation is regulated through complex feedback mechanisms under normal and stressful conditions.
Contribution
The study reveals multistability in translation initiation dynamics using kinetic modeling and structural analysis.
Findings
The model exhibits ultrasensitivity and bistability under normal conditions.
Under integrated stress response, the model shows tristability linked to translation recovery and attenuation.
Hidden feedback loops regulate translation initiation and termination dynamics.
Abstract
Protein synthesis involves translation initiation, elongation, termination, and ribosome recycling, and each step is controlled intricately by many signaling proteins. Translation initiation can be compactly categorized into two mechanisms: primary and secondary. The primary mechanism involves the recruitment of three important eukaryotic initiation factors, eIF2-GDP, eIF5, and eIF2B, and their interactions, followed by the GDP-GTP exchange by eIF2B to form an active dimer eIF2-GTP. The dimer binds with Met-tRNA to form a robust ternary complex (TC). The secondary mechanism closely mirrors the primary reaction mechanism, except that the interactions of eIF2B and eIF5 happen with the TC to form complexes. These interactions happen with high fidelity and precision, failing which fail-safe mechanisms are invoked instantaneously to delay the initiation process. In this work, we build a…
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Taxonomy
TopicsRNA and protein synthesis mechanisms · Protein Structure and Dynamics · CRISPR and Genetic Engineering