Molecular Bases and Specificity behind the Activation of the Immune System OAS/RNAse L Pathway by Viral RNA

TL;DR

This paper explores how the immune system's OAS/RNase L pathway is activated by viral RNA using molecular simulations.

Contribution

The study reveals structural and energetic details of OAS activation by RNA and the impact of RNA mutations.

Findings

RNA binding induces an allosteric activation of OAS.

Free energy profiles show RNA-dependent conformational changes in OAS.

Certain RNA mutations reduce OAS activation by altering the protein-RNA interface.

Abstract

The first line of defense against invading pathogens usually relies on innate immune systems. In this context, the recognition of exogenous RNA structures is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turn triggers the activity of RNase L and, thus, cleaves cellular and viral RNA. In this contribution, by using long-range molecular dynamics simulations, complemented with enhanced sampling techniques, we elucidate the structural features leading to the activation of OAS by interaction with a model double-strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in the presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to downregulate OAS activation, in shaping the protein/nucleic acid interface and the conformational landscape of OAS is also analyzed.

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