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

• DOI: 10.1126/science.abf3546
• Publication Date: 2021-05-13T19:15:18Z
• Authors: Pramod R. Bhatt; Alain Scaiola; Gary Loughran; Marc Leibundgut; Annika Kratzel; Romane Meurs; René Dreos; Kate M. O’Connor; Angus McMillan; Jeffrey W. Bode; Volker Thiel; David Gatfield; John F. Atkins; Nenad Ban
• Keywords: Models, Molecular; Ribosomal Proteins; Protein Folding; Animals; Antiviral Agents/pharmacology; Codon, Terminator; Coronavirus RNA-Dependent RNA Polymerase/biosynthesis; Coronavirus RNA-Dependent RNA Polymerase/chemistry; Coronavirus RNA-Dependent RNA Polymerase/genetics; Cryoelectron Microscopy; Fluoroquinolones/pharmacology; Frameshifting, Ribosomal/drug effects; Genome, Viral; Humans; Image Processing, Computer-Assisted; Models, Molecular; Nucleic Acid Conformation; Open Reading Frames; Protein Folding; RNA, Messenger/chemistry; RNA, Messenger/genetics; RNA, Messenger/metabolism; RNA, Ribosomal, 18S/chemistry; RNA, Ribosomal, 18S/genetics; RNA, Ribosomal, 18S/metabolism; RNA, Viral/chemistry; RNA, Viral/genetics; RNA, Viral/metabolism; Ribosomal Proteins/metabolism; Ribosomes/metabolism; Ribosomes/ultrastructure; SARS-CoV-2/drug effects; SARS-CoV-2/genetics; SARS-CoV-2/physiology; Viral Proteins/biosynthesis; Viral Proteins/chemistry; Viral Proteins/genetics; Virus Replication/drug effects; Coronavirus RNA-Dependent RNA Polymerase; SARS-CoV-2; Cryoelectron Microscopy; Frameshifting, Ribosomal; Genome, Viral; Antiviral Agents; 3. Good health; Open Reading Frames; Codon, Terminator; Image Processing, Computer-Assisted; RNA, Ribosomal, 18S; Animals; Humans; Nucleic Acid Conformation; RNA, Viral; RNA, Messenger; Ribosomes; Research Articles; Fluoroquinolones

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