Role of Q675H Mutation in Improving SARS-CoV-2 Spike Interaction with the Furin Binding Pocket.

Anna Bertelli,Arnaldo Caruso,Massimo Ciccozzi,Giovanni Campisi,Francesca Caccuri,Serena Messali,Maria Milanesi,Pasqualina D’Ursi,Marta Giovanetti

doi:10.3390/v13122511

Abstract

Genotype screening was implemented in Italy and showed a significant prevalence of new SARS-CoV-2 mutants carrying Q675H mutation, near the furin cleavage site of spike protein. Currently, this mutation, which is expressed on different SARS-CoV-2 lineages circulating worldwide, has not been thoughtfully investigated. Therefore, we performed phylogenetic and biocomputational analysis to better understand SARS-CoV-2 Q675H mutants’ evolutionary relationships with other circulating lineages and Q675H function in its molecular context. Our studies reveal that Q675H spike mutation is the result of parallel evolution because it arose independently in separate evolutionary clades. In silico data show that the Q675H mutation gives rise to a hydrogen-bonds network in the spike polar region. This results in an optimized directionality of arginine residues involved in interaction of spike with the furin binding pocket, thus improving proteolytic exposure of the viral protein. Furin was predicted to have a greater affinity for Q675H than Q675 substrate conformations. As a consequence, Q675H mutation could confer a fitness advantage to SARS-CoV-2 by promoting a more efficient viral entry. Interestingly, here we have shown that Q675H spike mutation is documented in all the VOCs. This finding highlights that VOCs are still evolving to enhance viral fitness and to adapt to the human host. At the same time, it may suggest Q675H spike mutation involvement in SARS-CoV-2 evolution.

Highlights

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan, China, and spread all around the world causing the coronavirus disease 19 (COVID-19) pandemic [1]
All the variant of concern (VOC) are characterized by a typical mutational pattern, in which most of these mutations are located in the spike receptor binding domain (RBD), the most variable part of the coronavirus genome [7,8], leading to an increased affinity to human angiotensin-converting enzyme
From the end of January 2021 to the end of March 2021, we sequenced by Sanger 228 samples from SARS-CoV-2 positive patients with Cycle threshold (Ct) values < 30 (Ct range = 14–27,5; Ct median = 17.5)

Summary

Introduction

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan, China, and spread all around the world causing the coronavirus disease 19 (COVID-19) pandemic [1]. In October 2020, after the first pandemic wave, the United Kingdom faced a rapid rise in positive COVID-19 cases. In the same period, in South Africa, Brazil, and the United States of America, new circulating lineages were described for the first time, respectively designated as B.1.351 [4], P1 descending from B.1.1.28 lineage [5], and B.1.427/B.1.429 [6]. These last variants were named as VOC because their polymorphisms enhance viral transmissibility and may enable the viral escape from vaccine-elicited neutralizing antibodies. All the VOCs are characterized by a typical mutational pattern, in which most of these mutations are located in the spike receptor binding domain (RBD), the most variable part of the coronavirus genome [7,8], leading to an increased affinity to human angiotensin-converting enzyme

Methods

Results

Discussion

Conclusion