SR/RS Motifs as Critical Determinants of Coronavirus Life Cycle

Abstract

SR/RS domains are found in almost all eukaryotic genomes from C. elegans to human. These domains are thought to mediate interactions between proteins but also between proteins and RNA in complex networks associated with mRNA splicing, chromatin structure, transcription, cell cycle and cell structure. A precise and tight regulation of their function is achieved through phosphorylation of a number of serine residues within the SR/RS motifs by the Serine-Arginine protein kinases (SRPKs) that lead to delicate structural alterations. Given that coronavirus N proteins also contain SR/RS domains, we formulate the hypothesis that the viruses exploit the properties of these motifs to promote unpacking of viral RNA and virion assembly.

Keywords: N protein; SR protein kinases; SR/RS motifs; capsid assembly/disassembly; coronaviruses.

FIGURE 1

Domain organization of N protein. NTD, N-terminal RNA binding domain; SR, Serine/Arginine domain; CTD, C-terminal RNA binding domain; N3, C-terminal domain.

FIGURE 2

(A) Newly synthesized N proteins are prone to aggregation when they are unmodified (left panel). Phosphorylation of the SR/RS dipeptides by SRPKs (and possibly other cellular kinases) prevents aggregation and leads to the assembly of soluble dimers with the acidic carboxyl-tail domains (N3) exposed (right panel). (B) A provisional model of “encapsidosome” assembly. The exposed N3 domains interact with the M protein endodomain. The M protein endodomain binds also to the packaging signal (PS) of genomic RNA, while we propose that the genomic RNA-M protein complex carries a protein phosphatase activity (PPase). The phosphatase would dephosphorylate the SR/RS domains of the nearby associated dimers thus allowing the NTD and CTD interaction with genomic RNA. Furthermore, dephosphorylation would result in a conformational change of N proteins, dissociation of the N3 domains from the M protein endodomain and beginning of genomic RNA packaging. The dissociation of the N protein dimer from the M protein would leave space for a new N dimer to bind. The packaging process will go on with N protein dimers binding continuously to diverse sequences of genomic RNA until the entire RNA is enwrapped.