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Journal Articles International Journal of Molecular Sciences Year : 2023

Molecular Determinants of Fibrillation in a Viral Amyloidogenic Domain from Combined Biochemical and Biophysical Studies

Juliet F Nilsson
Hakima Baroudi
  • Function : Author
Frank Gondelaud
  • Function : Author
Giulia Pesce
Christophe Bignon
  • Function : Author
Denis Ptchelkine
Joseph Chamieh
Hervé Cottet
Andrey V Kajava

Abstract

The Nipah and Hendra viruses (NiV and HeV) are biosafety level 4 human pathogens classified within the Henipavirus genus of the Paramyxoviridae family. In both NiV and HeV, the gene encoding the Phosphoprotein (P protein), an essential polymerase cofactor, also encodes the V and W proteins. These three proteins, which share an intrinsically disordered N-terminal domain (NTD) and have unique C-terminal domains (CTD), are all known to counteract the host innate immune response, with V and W acting by either counteracting or inhibiting Interferon (IFN) signaling. Recently, the ability of a short region within the shared NTD (i.e., PNT3) to form amyloid-like structures was reported. Here, we evaluated the relevance of each of three contiguous tyrosine residues located in a previously identified amyloidogenic motif (EYYY) within HeV PNT3 to the fibrillation process. Our results indicate that removal of a single tyrosine in this motif significantly decreases the ability to form fibrils independently of position, mainly affecting the elongation phase. In addition, we show that the C-terminal half of PNT3 has an inhibitory effect on fibril formation that may act as a molecular shield and could thus be a key domain in the regulation of PNT3 fibrillation. Finally, the kinetics of fibril formation for the two PNT3 variants with the highest and the lowest fibrillation propensity were studied by Taylor Dispersion Analysis (TDA). The results herein presented shed light onto the molecular mechanisms involved in fibril formation.
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Dates and versions

hal-03952101 , version 1 (23-01-2023)

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Juliet F Nilsson, Hakima Baroudi, Frank Gondelaud, Giulia Pesce, Christophe Bignon, et al.. Molecular Determinants of Fibrillation in a Viral Amyloidogenic Domain from Combined Biochemical and Biophysical Studies. International Journal of Molecular Sciences, 2023, 24 (1), pp.399. ⟨10.3390/ijms24010399⟩. ⟨hal-03952101⟩

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