INVESTIGADORES
DE PRAT GAY Gonzalo
artículos
Título:
Conformational Isomerization Involving Conserved Proline Residues Modulates Oligomerization of the NS1 Interferon Response Inhibitor from the Syncytial Respiratory Virus
Autor/es:
CONCI, JULIETA; ALVAREZ-PAGGI, DAMIAN; DE OLIVEIRA, GUILHERME A. P.; PAGANI, TALITA D.; ESPERANTE, SEBASTIAN A.; BORKOSKY, SILVINA S.; ARAN, MARTIN; ALONSO, LEONARDO G.; MOHANA-BORGES, RONALDO; PRAT-GAY, GONZALO DE
Revista:
BIOCHEMISTRY
Editorial:
AMER CHEMICAL SOC
Referencias:
Año: 2019
ISSN:
0006-2960
Resumen:
Interferon response suppression by the respiratory syncytial virus relies on two unique nonstructural proteins, NS1 and NS2, that interact with cellular partners through high-order complexes. We hypothesized that two conserved proline residues, P81 and P67, participate in the conformational change leading to oligomerization. We found that the molecular dynamics of NS1 show a highly mobile C-terminal helix, which becomes rigid upon in silico replacement of P81. A soluble oligomerization pathway into regular spherical structures at lowionic strengths competes with an aggregation pathway at high ionic strengths with an increase in temperature. P81A requires higher temperatures to oligomerize and has a small positive effect on aggregation,while P67A is largely prone to aggregation. Chemical denaturation shows a first transition, involving a high fluorescence andellipticity change corresponding to both a conformational change and substantial effects on the environment of its singletryptophan, that is strongly destabilized by P67A but stabilized by P81A. The subsequent global cooperative unfoldingcorresponding to the main β-sheet core is not affected by the proline mutations. Thus, a clear link exists between the effect ofP81 and P67 on the stability of the first transition and oligomerization/aggregation. Interestingly, both P67 and P81 are locatedfar away in space and sequence from the C-terminal helix, indicating a marked global structural dynamics. This provides amechanism for modulating the oligomerization of NS1 by unfolding of a weak helix that exposes hydrophobic surfaces, linked tothe participation of NS1 in multiprotein complexes.