Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop

Abstract

The 2019 novel coronavirus (2019-nCoV/SARS-CoV-2) originally arose as part of a major outbreak of respiratory disease centered on Hubei province, China. It is now a global pandemic and is a major public health concern. Taxonomically, SARS-CoV-2 was shown to be a Betacoronavirus (lineage B) closely related to SARS-CoV and SARS-related bat coronaviruses, and it has been reported to share a common receptor with SARS-CoV (ACE-2). Subsequently, betacoronaviruses from pangolins were identified as close relatives to SARS-CoV-2. Here, we perform structural modeling of the SARS-CoV-2 spike glycoprotein. Our data provide support for the similar receptor utilization between SARS-CoV-2 and SARS-CoV, despite a relatively low amino acid similarity in the receptor binding module. Compared to SARS-CoV and all other coronaviruses in Betacoronavirus lineage B, we identify an extended structural loop containing basic amino acids at the interface of the receptor binding (S1) and fusion (S2) domains. We suggest this loop confers fusion activation and entry properties more in line with betacoronaviruses in lineages A and C, and be a key component in the evolution of SARS-CoV-2 with this structural loop affecting virus stability and transmission.

Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins

“…The higher cross-neutralizing capacity of the tested IVIG preparations against SARS-CoV and SARS-CoV-2 than MERS-CoV may be explained by higher sequence identity of the S proteins of circulating mild human coronaviruses (HCoV-OC43 and HCoV-HKU1) and SARS-CoV and SARS-CoV-2 compared to MERS-CoV (32%-33% vs. 23%-25) 14,15 . Additionally, differences in specific domains of the S protein between SARS-CoV and SARS-CoV-2 might explain higher cross-reactivity of the tested IVIG against SARS-CoV-2 compared to SARS-CoV (80%-90% vs. 40%-60%).…”

“…The amino-acid sequence identity among the S proteins of human betacoronaviruses causing mild (HCoV-OC43 and HCoV-HKU1) and severe (SARS-CoV, SARS-CoV-2, and MERS-CoV) respiratory infections varies between 22% and 33% 10 . However, the S proteins of SARS-CoV and SARS-CoV-2 share 77% amino-acid identity 14 and more than 90% RNA sequence homology 15 . Cross-reactivity in antigenic responses has been described among human coronaviruses of the same genus, particularly betacoronaviruses.…”

The PRRA insert at the S1/S2 site modulates cellular tropism of SARS-CoV-2 and ACE2 usage by the closely related Bat raTG13

“…2) A distinct four amino acid insert within the spike (S) protein (underlined, SPRRAR↓S) between the S1 receptor binding subunit and the S2 fusion subunit presumably creates a functional polybasic (furin) cleavage site. This novel S1/S2 site of SARS-CoV-2 Spike is hypothesized to affect the stability, transmission and/or host range of the virus (Jaimes et al, 2020a;Jaimes et al, 2020b).…”

Recombination in Sarbecovirus lineage and mutations/insertions in spike protein linked to the emergence and adaptation of SARS-CoV-2

“…Major genetic variations in these genes, particularly in spike (S) gene, seemed essential for the transition from animal-to-human transmission to human-to-human transmission, which eventually caused the outbreak of 2019-nCoV (Su et al, 2016;Luk et al 2019;Jaimes et al, 2020). Details of the genome and gene recombination analyses are given in Table 1 and Table 2 respectively.…”