Relevance of Ebola virus VP35 homo-dimerization on the type I interferon cascade inhibition

Di Palma, Francesco
First
;
Ramaswamy, Venkata Krishnan;Corona, Angela;Frau, Aldo;Fanunza, Elisa;Vargiu, Attilio V;Tramontano, Enzo
Penultimate
;
Ruggerone, Paolo
Last
2019

Abstract

Ebola virus high lethality relies on its ability to efficiently bypass the host innate antiviral response, which senses the viral dsRNA through the RIG-I receptor and induces type I interferon a/b production. In the bypassing action, the Ebola virus protein VP35 plays a pivotal role at multiple levels of the RIG-I cascade, masking the viral 50 -triphosphorylated dsRNA from RIG-I, and interacting with other cascade components. The VP35 type I interferon inhibition is exerted by the C-terminal domain, while the N-terminal domain, containing a coiled-coil region, is primarily required for oligomerization. However, mutations at key VP35 residues L90/93/107A (VP35-3m) in the coiled-coil region were reported to affect oligomerization and reduce type I interferon antagonism, indicating a possible but unclear role of homo-oligomerization on VP35 interaction with the RIG-I pathway components. In this work, we investigated the VP35 dimerization thermodynamics and its contribution to type I interferon antagonism by computational and biological methods. Focusing on the coiled-coil region, we combined coarse-grained and all-atom simulations on wild type VP35 and VP35-3m homo-dimerization. According to our results, wild type VP35 coiled-coil is able to self-assemble into dimers, while VP35-3m coiled-coil shows poor propensity to even dimerize. Free-energy calculations confirmed the key role of L90, L93 and L107 in stabilizing the coiled-coil homo-dimeric structure. In vitro type I interferon antagonism studies, using full-length wild type VP35 and VP35-3m, revealed that VP35 homo-dimerization is an essential preliminary step for dsRNA binding, which appears to be the main factor of the VP35 RIG-I cascade inhibition, while it is not essential to block the other steps.
2019
Inglese
27
1
13
13
https://journals.sagepub.com/doi/10.1177/2040206619889220
Esperti anonimi
internazionale
scientifica
Models/projections, mutations, Filoviridae
no
Di Palma, Francesco; Daino, Gian Luca; Ramaswamy, Venkata Krishnan; Corona, Angela; Frau, Aldo; Fanunza, Elisa; Vargiu, Attilio V; Tramontano, Enzo; Ruggerone, Paolo
1.1 Articolo in rivista
info:eu-repo/semantics/article
1 Contributo su Rivista::1.1 Articolo in rivista
262
9
open
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