Conformational isomerization involving conserved proline residues modulates oligomerization of the NS1 interferon response inhibitor from the syncytial respiratory virus

CONCI, JULIETA; ALVAREZ-PAGGI, DAMIAN; DE OLIVEIRA, GUILHERME A. P.; DUARTE PAGANI, TALITA; ESPERANTE, SEBASTIÁN ANDRÉS; BORKOSKY, SILVIA SUSANA; ARAN, MARTÍN; ALONSO, LEONARDO GABRIEL; MOHANA-BORGES, RONALDO; PRAT-GAY, GONZALO DE

BIOCHEMISTRY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2019

0006-2960

The interferon response suppression by the respiratory syncytial virus relies on twounique non-structural proteins, NS1 and NS2, that interact with cellular partners through highorder complexes. We hypothesized that two conserved proline residues, P81 and P67,participate in the conformational change leading to oligomerization. We found that moleculardynamics of NS1 show a highly mobile C-terminal helix, which become rigid upon in silicoreplacement of P81. A soluble oligomerization pathway into regular spherical structures at lowionic strength competes with an aggregation pathway at high ionic strength upon temperatureincrease. P81A requires higher temperatures to oligomerize and has a small positive effecton aggregation, while P67A is largely prone to aggregation. Chemical denaturation shows afirst transition, involving a large fluorescence and ellipticity change corresponding to both aconformational change and substantial effects on the environment of its single tryptophan,that is strongly destabilized in P67A but stabilized by P81A. The subsequent globalcooperative unfolding corresponding to the main ß-sheet core is not affected by the prolinemutations. Thus, a clear link exists between the effect of P81 and P67 on the stability of thefirst transition and oligomerization/aggregation. Interestingly, both P67 and P81 are locatedfar away in space and sequence from the C-terminal helix, indicating a marked globalstructural dynamics. This provide a mechanism for modulating the oligomerization of NS1 byunfolding of a weak helix that exposes hydrophobic surfaces, linked to the participation ofNS1 in multiprotein complexes.