Ensemble description of the intrinsically disordered N-terminal domain of the Nipah virus P/V protein from combined NMR and SAXS - Archive ouverte HAL Access content directly
Journal Articles Scientific Reports Year : 2020

Ensemble description of the intrinsically disordered N-terminal domain of the Nipah virus P/V protein from combined NMR and SAXS


Using SAXS and NMR spectroscopy, we herein provide a high-resolution description of the intrinsically disordered N-terminal domain (PNT, aa 1-406) shared by the Nipah virus (NiV) phosphoprotein (P) and V protein, two key players in viral genome replication and in evasion of the host innate immune response, respectively. The use of multidimensional NMR spectroscopy allowed us to assign as much as 91% of the residues of this intrinsically disordered domain whose size constitutes a technical challenge for NMR studies. Chemical shifts and nuclear relaxation measurements provide the picture of a highly flexible protein. The combination of SAXS and NMR information enabled the description of the conformational ensemble of the protein in solution. The present results, beyond providing an overall description of the conformational behavior of this intrinsically disordered region, also constitute an asset for obtaining atomistic information in future interaction studies with viral and/or cellular partners. The present study can thus be regarded as the starting point towards the design of inhibitors that by targeting crucial protein-protein interactions involving PNT might be instrumental to combat this deadly virus. The Nipah virus (NiV), together with its close relative Hendra virus (HeV), is a zoonotic paramyxovirus responsible for severe encephalitis in humans. The NiV and HeV have been classified in the Henipavirus genus 1 that also comprises the later on discovered Cedar virus (CedV) 2. Because of their high pathogenic power, broad host range, high interspecies transmission and lack of therapeutics and vaccines, henipaviruses are classified as bio-security level 4 (BSL-4) pathogens and are considered as potential bio-terrorism agents. The genome of henipaviruses is made of a non-segmented, single-stranded RNA molecule of negative polarity that is encapsidated by a regular array of nucleoprotein (N) monomers to form a helical nucleocapsid. This N:RNA complex, and not naked RNA, is the substrate used by the viral polymerase for both transcription and replication. The viral polymerase is a complex consisting of the large (L) protein, which bears all the enzymatic activities, and the phosphoprotein (P). Through its interaction with both L and the nucleocapsid, the P protein acts as a tether and recruits L onto the N:RNA template. In addition, P also serves as a chaperon for both L 3 and N in that it is required for proper folding/maturation of L and maintains N in a monomeric, RNA-free form 4. Therefore P is a pivotal protein endowed with multiple functions critical for both transcription and replication. The repertoire of P functions is further expanded by the peculiar coding capacity of the P gene. Indeed, beyond the P protein, the P gene also codes for the V and W proteins that are generated through the addition of either one (protein V) or two (protein W) non-templated guanosines at the editing site of the P messenger. The addition of these guanosines triggers a downstream frame-shift. The P, V, and W proteins therefore share a OPEN
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hal-03004864 , version 1 (18-12-2020)





Marco Schiavina, Edoardo Salladini, Maria Grazia Murrali, Giancarlo Tria, Isabella Felli, et al.. Ensemble description of the intrinsically disordered N-terminal domain of the Nipah virus P/V protein from combined NMR and SAXS. Scientific Reports, 2020, 10 (1), ⟨10.1038/s41598-020-76522-3⟩. ⟨hal-03004864⟩
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