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Abstract
Phosphoprotein is the main cofactor of the viral RNA polymerase of Mononegavirales It is involved in multiple interactions that are essential for the polymerase function. Most prominently it positions the polymerase complex onto the nucleocapsid, but also acts as a chaperone for the nucleoprotein. Mononegavirales phosphoproteins lack sequence conservation, but contain all large disordered regions. We show here that N- and C-terminal intrinsically disordered regions account for 80% of the phosphoprotein of the respiratory syncytial virus. But these regions display marked dynamic heterogeneity. Whereas almost stable helices are formed C terminally to the oligomerization domain, extremely transient helices are present in the N-terminal region. They all mediate internal long-range contacts in this non-globular protein. Transient secondary elements together with fully disordered regions also provide protein binding sites recognized by the respiratory syncytial virus nucleoprotein and compatible with weak interactions required for the processivity of the polymerase.
Highlights
Human respiratory syncytial virus,3 a member of the family Pneumoviridae [1] and order Mononegavirales (MNV), is the main viral cause of lower respiratory tract illness worldwide, and the main agent responsible for bronchiolitis and pneumonia in infants [2]
During transcription and replication it tethers the L protein to the nucleocapsid (NC), consisting of the genomic RNA packaged by the nucleoprotein (N), by direct interaction with N [13,14,15,16]. Human respiratory syncytial virus (hRSV) P binds to the transcription antitermination factor M2-1 [17,18,19]
This is the signature of intrinsically disordered proteins (IDPs) and regions (IDRs) [29]
Summary
Human respiratory syncytial virus (hRSV), a member of the family Pneumoviridae [1] and order Mononegavirales (MNV), is the main viral cause of lower respiratory tract illness worldwide, and the main agent responsible for bronchiolitis and pneumonia in infants [2]. The hRSV RNA-dependent RNA complex (RdRp) constitutes a virus-specific target with specific protein-protein interactions that have not all been investigated in detail [7]. It uses the nonsegmented single-stranded negative sense RNA genome of hRSV as a template. The viral RdRp is found in specific inclusion bodies [8], which have been shown to be transcription and replication centers for other Mononegavirales, e.g. rabies [9] and vesicular stomatitis viruses [10]. Our aim was to get a deeper insight into the structural plasticity of P and to explore the role of transiently ordered regions for interactions with hRSV RdRp proteins, here with N, by using NMR spectroscopy
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