Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome

By P. R. Bhatt, A. Scaiola, G. Loughran, M. Leibundgut, A. Kratzel, Romane Meurs, René Dreos, Kate M. O’Connor, Angus E. McMillan, J. Bode and 4 more. Science, 2020

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Shifting frames to make more proteins Severe acute respiratory syndrome coronavirus 2 critically depends on the ribosomal frameshifting that occurs between two large open reading frames in its genomic RNA for expression of viral replicase. Programmed frameshifting occurs during translation, when the ribosome encounters a stimulatory pseudoknot RNA fold. Using a combination of cryo–electron microscopy and biochemistry, Bhatt et al. revealed that the pseudoknot resists unfolding as it lodges at the entry of the ribosomal messenger RNA channel. This causes back slippage of the viral RNA, resulting in a minus-1 shift of the reading frame of translation. A partially folded nascent viral polyprotein forms specific interactions inside the ribosomal tunnel that can influence the efficiency of frameshifting. Science, abf3546, this issue p. 1306 A pseudoknot impedes ribosome progression to promote frameshifting in SARS-CoV-2, which allows synthesis of the viral proteins. Programmed ribosomal frameshifting is a key event during translation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome that allows synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here, we present the cryo–electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal messenger RNA (mRNA) channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.

Subfields: Cardiology and Cardiovascular Medicine, Ecology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6510bcca802110a9ed6a24e80b0470b3ff3348ab