In-Silico analysis reveals lower transcription efficiency of C241T variant of SARS-CoV-2 with host replication factors MADP1 and hnRNP-1

Abstract

Novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has claimed more than 3.3 million lives worldwide and still counting. As per the GISAID database, the genomics of SARS-CoV-2 has been extensively studied, with more than 500 genome submissions per day. Out of several hotspot mutations within the SARS-CoV-2 genome, recent research has focused mainly on the missense variants. Moreover, significantly less attention has been accorded to delineate the role of the untranslated regions (UTRs) of the SARS-CoV-2 genome in the disease progression and etiology. One of the most frequent 5’ UTR variants in the SARS-CoV-2 genome is the C241T, with a global frequency of more than 95 %. In the present study, the effect of the C241T mutation has been studied with respect to the changes in RNA structure and its interaction with the host replication factors MADP1 Zinc finger CCHC-type and RNA-binding motif 1 (hnRNP1). The results obtained from molecular docking and molecular dynamics simulation indicated weaker interaction of C241T mutant stem-loops with the host transcription factor MADP1, indicating a reduced replication efficiency. The results are also correlated with increased recovery rates and decreased death rates of global SARS-CoV-2 cases.

Host and Viral Zinc-Finger Proteins in COVID-19

“…The 5′ UTRs interact with host factors and such interaction plays important roles in the replication, disease evolution, and aetiology [ 101 , 102 , 103 ]. In particular, during the intermittent replication process of Sars-CoV-1 genome, SL1 (RNA stem-loop 1), and SL2 support viral replication and transcription by interacting with the host MADP1 aided by nsp1 protein [ 103 , 104 ].…”

“…MADP1 encompasses two conserved RNA-binding domains, the RNA recognition motif 1 and a Cys 2 HisCys ZNF [ 104 ] and has a critical role in determining the replication efficiency within host cells [ 103 ].…”

“…One of the most frequent 5′ UTR variants in the SARS-CoV-2 genome is the C241T emerged in March 2020 [ 107 ]. Such mutation has an undefined significance [ 108 ], however its effects have been studied in-silico [ 104 ]. The study shows how C241T mutation changes the folding of SL4 RNA decreasing the stability of 5′ UTR and affecting its interaction with host transcription factor MADP1.…”

Defective ORF8 dimerization in SARS-CoV-2 delta variant leads to a better adaptive immune response due to abrogation of ORF8-MHC1 interaction

“…Several other mutations like D614G in modulating higher spike infectivity and density, E484K for decreased antibody neutralization, N501Y and K417N for altering spike interacting with ACE receptor and antibodies derived from humans were reported [13,17,42]. There are several mutations which favors the host for example C241T, where viral replication efficiency with respect to host replication factors in decreased [8]. Recent reports suggest that NTD (N-Terminal Domain) is known to be supersite for antibody-mediated binding [10,25,33].…”

Characteristics of SARS-CoV-2 transmission in a medium-sized city with traditional communities during the early COVID-19 epidemic in China

“…C241T was identified as a SNP or iSNV in multiple family/community transmissions and multiple non-clustered cases. According to statistics of the China National Center for Bioinformation-National Genomics Data Center (CNCB-NGDC), C241T rapidly replaced the corresponding wild-type allele in the virus population and became a feature SNP of Clade G since February 2020, and some studies have shown that C241 may confer an advantage to SARS-CoV-2 transmission ( Chaudhari et al 2021 ; Luo et al 2021 ). Considering that C241T was relatively prevalent in the Anyang virus genomes and it could not be ruled out that it arose spontaneously, we excluded it from the family/community-specific variants.…”