How order and disorder within paramyxoviral nucleoproteins and phosphoproteins orchestrate the molecular interplay of transcription and replication

Abstract

In this review, we summarize computational and experimental data gathered so far showing that structural disorder is abundant within paramyxoviral nucleoproteins (N) and phosphoproteins (P). In particular, we focus on measles, Nipah, and Hendra viruses and highlight both commonalities and differences with respect to the closely related Sendai virus. The molecular mechanisms that control the disorder-to-order transition undergone by the intrinsically disordered C-terminal domain (N) of their N proteins upon binding to the C-terminal X domain (XD) of the homologous P proteins are described in detail. By having a significant residual disorder, N-XD complexes are illustrative examples of "fuzziness", whose possible functional significance is discussed. Finally, the relevance of N-P interactions as promising targets for innovative antiviral approaches is underscored, and the functional advantages of structural disorder for paramyxoviruses are pinpointed.

Structure of the Respiratory Syncytial Virus Polymerase Complex

“…The RSV P Tetramer Grips L Using an Unusual Tentacular Arrangement As expected from previous experiments, residues 131-151 of RSV P formed a tetrameric coiled coil (Castagné et al, 2004;Llorente et al, 2006;Pereira et al, 2017). Historically, regions outside of this oligomerization domain have not been structurally well characterized because of their intrinsic flexibility (Longhi et al, 2017). However, the interaction of P with L stabilized ordered conformations of the C-terminal regions of P, allowing them to be resolved for the first time.…”

Phase transition and amyloid formation by a viral protein as an additional molecular mechanism of virus-induced cell toxicity

“…Since the P protein is an essential component of the replicative complex of Mononegavirales, and since the presence of large IDRs is a wide spread and conserved property in Mononegavirales P proteins [16,[76][77][78][79][80][81][82][83][84][85][86][87][88][89], it is conceivable that the ability to undergo phase separation and transition is not unique to HeV P/V. As such, these results promise to have broad implications on a large number of important human pathogens.…”

Nipah shell disorder, modes of infection, and virulence

“…Structurally, N protein contains two globular domains, the N-terminal (N NTD , residues 32-258) and Cterminal (N CTD , residues 259-371) domains decorated with two projections, N-terminal (NT ARM , residues 1-31) and C-terminal subdomains (CT ARM , residues 372-383), and a long and highly disordered C-terminal tail (N TAIL , residues 384-532) that protrudes outside the nucleocapsid. These different structural parts of N have divergent biological functions, where N NTD and N CTD enwrap the genomic RNA to protect it against nucleases [37][38][39][40][41], NT ARM and CT ARM from adjacent protomers are exchanged to ensure stable lateral contacts needed for stabilization of the N homopolymer 2005) [37][38][39][40][41], and a highly disordered N tail is utilized in binding to the C-terminal domain of the phosphoprotein P (P XD ) [42][43][44][45][46][47][48][49][50][51][52][53][54]. Therefore, the viral shell contains N as a major nucleocapsid protein alongside with the phosphoprotein, P, and a large protein L that serves as an RNA polymerase during viral replication [6,8,52,55].…”