Structure and sequence characteristics of 5'-stem-loop 1 modulate the escape from nsp1-mediated repression in...

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• SARS-CoV-2 variants emerge with significant clinical relevance due to alterations in viral proteins and RNA structures.
• The 5'-untranslated region (UTR) and non-structural protein 1 (nsp1) are critical for viral genome translation, yet their co-evolutionary dynamics remain incompletely understood.

Purpose of the Study:

• To structurally and functionally characterize frequent mutations in the 5'-UTR stem-loop 1 (SL1) and nsp1 of SARS-CoV-2.
• To elucidate the co-evolutionary relationship between SL1 RNA structures and nsp1 variants in regulating viral translation.

Main Methods:

• Investigated mutations in SL1 and nsp1 using structural and functional analyses.
• Analyzed mutation C21U in SL1 for changes in loop dynamics and nsp1 repression escape.
• Performed mutation analyses on SL1 pyrimidine loop and apical helix to identify sequence motifs for nsp1 repression escape.

Main Results:

• Mutation C21U in SL1 exhibited altered dynamics and reduced escape from nsp1 repression.
• Identified specific sequence motifs in SL1 that facilitate escape from nsp1 repression, influenced by structural context.
• The circulating nsp1 variant S135R demonstrated increased sensitivity to sequence and structural variations in the SL1 apical loop compared to wild-type nsp1.

Conclusions:

• The study provides novel insights into the structure-function relationships governing the co-evolution of SARS-CoV-2 RNA structures and proteins.
• Understanding these interactions is vital for comprehending viral adaptation and the emergence of new variants.