Longer linker regions in sarbecovirus Nsp1 correlate with increased translation inhibition efficiency compared to shorter linkers in merbecovirus Nsp1.
Structural variations in the linker regions of coronavirus Nsp1 proteins correlate with translation inhibition efficiency, providing insights into viral evolutionary adaptations.
Abstract Nonstructural protein 1 (Nsp1) is a key virulence factor of coronaviruses, and its stable binding to the 40S ribosomal mRNA entry channel facilitates multiple functions, including suppression of host immune responses and degradation of host mRNA. To understand the structural basis of the conserved protein across viral lineages, we determined the cryo-EM structures of Nsp1–40S complexes of four coronaviruses from wild animals. Our results show that all Nsp1 proteins engage the mRNA entry channel via their C-terminal domain (CTD), but do not fully restrict the rotational mobility of the 40S head, which retains ∼5° of movement and repositions the Nsp1 linker region. Comparative analysis revealed distinct patterns in the linker regions connecting the N- and CTDs. Sarbecovirus Nsp1 contains a longer linker, whereas the merbecovirus Nsp1 adopts a shorter linker that navigates structural constraints more readily. Functionally, we find that linker length correlates with translation inhibition efficiency, suggesting a structural tuning mechanism. Additionally, variations in linker and helix 1 of the CTD among different lineages may serve as molecular markers for viral classification. Together, our results provide a comparative structural framework for understanding how coronavirus Nsp1 proteins modulate host translation and reflect evolutionary adaptations in ribosome engagement.
Yan et al. (2026) studied this question. Longer linker regions in sarbecovirus Nsp1 correlate with increased translation inhibition efficiency compared to shorter linkers in merbecovirus Nsp1.