Abstract
The high sequence identity of the first SARS-CoV-2 samples collected in December 2019 at Wuhan did not foretell the emergence of novel variants in the United Kingdom, North and South America, India, or South Africa that drive the current waves of the pandemic. The viral spike receptor possesses two surface areas of high mutagenic plasticity: the supersite in its N-terminal domain (NTD) that is recognised by all anti-NTD antibodies and its receptor binding domain (RBD) where 17 residues make contact with the human Ace2 protein (angiotensin I converting enzyme 2) and many neutralising antibodies bind. While NTD mutations appear at first glance very diverse, they converge on the structure of the supersite. The mutations within the RBD, on the other hand, hone in on only a small number of key sites (K417, L452, E484, N501) that are allosteric control points enabling spike to escape neutralising antibodies while maintaining or even gaining Ace2-binding activity. The D614G mutation is the hallmark of all variants, as it promotes viral spread by increasing the number of open spike protomers in the homo-trimeric receptor complex. This review discusses the recent spike mutations as well as their evolution.
Highlights
When the first SARS-CoV-2 patients were tested in December 2019 in Wuhan, China, the sequences of the single-stranded RNA virus were almost identical (≥99.9%), defining the new sequence family known as the L clade [1–3]
By June 2020, barely six months into the pandemic, the L clade dwindled to only 7% outside of Asia, and the dominating sequence group became the rapidly evolving G clade harbouring, amongst other changes, the D614G mutation in the viral spike protein [4]
Each SARS-CoV-2 virus carries approximately 90 homo-trimeric spike receptors in its membrane that vary in height between 9 nm and 12 nm [5]
Summary
When the first SARS-CoV-2 patients were tested in December 2019 in Wuhan, China, the sequences of the single-stranded RNA virus were almost identical (≥99.9%), defining the new sequence family known as the L clade (reference sequence: EPI_ISL_402123) [1–3]. Each SARS-CoV-2 virus carries approximately 90 homo-trimeric spike receptors in its membrane that vary in height between 9 nm and 12 nm [5]. They define spread and tropism of the virus as well as its ability to evade the immune system, as most neutralising antibodies bind to the viral receptor. A variant of concern (VOC) is a mutated strain of the Wuhan virus (reference genome: NC_045512.2) [8] that possesses a higher transmissibility, causes a more severe disease progression, increases mortality, escapes antibody neutralization, and/or evades detection. As of 11 May 2021, Variants of Concern are B.1.1.7 (UK), B.1.351 (South Africa), P.1 (Brazil), and B.1.617 (India); the sole Variant of Interest is B.1.429/B.1.427 (USA), and Variants under Monitoring are B.1.526 (USA) and P.2 (Brazil). We explore the drivers behind the rapid accumulation of mutations in spike
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