RT Journal Article
SR Electronic
T1 Effect of the SARS-CoV-2 Delta-associated G15U mutation on the s2m element dimerization and its interactions with miR-1307-3p
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.02.10.528014
DO 10.1101/2023.02.10.528014
A1 Caylee L. Cunningham
A1 Caleb J. Frye
A1 Joseph A. Makowski
A1 Adam H. Kensinger
A1 Morgan Shine
A1 Ella J. Milback
A1 Patrick E. Lackey
A1 Jeffrey D. Evanseck
A1 Mihaela-Rita Mihailescu
YR 2023
UL http://biorxiv.org/content/early/2023/02/10/2023.02.10.528014.abstract
AB The stem loop 2 motif (s2m), a highly conserved 41-nucleotide hairpin structure in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, serves as an attractive therapeutic target that may have important roles in the virus life cycle or interactions with the host. However, the conserved s2m in Delta SARS-CoV-2, a previously dominant variant characterized by high infectivity and disease severity, has received relatively less attention than that of the original SARS-CoV-2 virus. The focus of this work is to identify and define the s2m changes between Delta and SARS-CoV-2 and subsequent impact of those changes upon the s2m dimerization and interactions with the host microRNA miR-1307-3p. Bioinformatics analysis of the GISAID database targeting the s2m element reveals a greater than 99% correlation of a single nucleotide mutation at the 15th position (G15U) in Delta SARS-CoV-2. Based on 1H NMR assignments comparing the imino proton resonance region of s2m and the G15U at 19°C, we find that the U15-A29 base pair closes resulting in a stabilization of the upper stem without overall secondary structure deviation. Increased stability of the upper stem did not affect the chaperone activity of the viral N protein, as it was still able to convert the kissing dimers formed by s2m G15U into a stable duplex conformation, consistent with the s2m reference. However, we find that the s2m G15U mutation drastically reduces the binding affinity of the host miR-1307-3p. These findings demonstrate that the observed G15U mutation alters the secondary structure of s2m with subsequent impact on viral binding of host miR-1307-3p, with potential consequences on the immune response.Competing Interest StatementThe authors have declared no competing interest.