Asn25 Deamidation as an Allosteric Tool to Increase IFNβ-1a Biological Activity.

Elisa Lipari, Simona Saporiti, Ivano Eberini, Luigia Massimo, Enrico Mazzarella, Giulia Anderloni, Mara Rossi, Fabio D'Amici, Carlo Pergola, Wolf Palinsky, Cosimo Walter D'Acunto, Fabio Centola

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2022 Jun

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Interferon beta (IFNβ) is a well-known cytokine, belonging to the type I family, that exerts antiviral, immunomodulatory, and antiproliferative activity. It has been reported that the artificially deamidated form of recombinant IFNβ-1a at Asn25 position shows an increased biological activity. As a deepening of the previous study, the molecular mechanism underlying this biological effect was investigated in this work by combining experimental and computational techniques. Specifically, the binding to IFNAR1 and IFNAR2 receptors and the canonical pathway of artificially deamidated IFNβ-1a molecule were analyzed in comparison to the native form. As a result, a change in receptor affinity of deamidated IFNβ-1a with respect to the native form was observed, and to better explore this molecular interaction, molecular dynamics simulations were carried out. Results confirmed, as previously hypothesized, that the N25D mutation can locally change the interaction network of the mutated residue but also that this effect can be propagated throughout the molecule. In fact, many residues not involved in the interaction with IFNAR1 in the native form participate to the recognition in the deamidated molecule, enhancing the binding to IFNAR1 receptor and consequently an increase of signaling cascade activation. In particular, a higher STAT1 phosphorylation and interferon-stimulated gene expression was observed under deamidated IFNβ-1a cell treatment. In conclusion, this study increases the scientific knowledge of deamidated IFNβ-1a, deciphering its molecular mechanism, and opens new perspectives to novel therapeutic strategies.

Citation

Elisa Lipari, Simona Saporiti, Ivano Eberini, Luigia Massimo, Enrico Mazzarella, Giulia Anderloni, Mara Rossi, Fabio D'Amici, Carlo Pergola, Wolf Palinsky, Cosimo Walter D'Acunto, Fabio Centola. Asn25 Deamidation as an Allosteric Tool to Increase IFNβ-1a Biological Activity. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2022 Jun;42(6):251-266