![]() Second, SARS-CoV-2 proteins have structurally divergent S1 receptor-binding domains (RBDs) that bind with relatively high affinity to human angiotensin-converting enzyme 2 (hACE2) ( 23, 24). First, SARS-CoV-2 S proteins have S1 amino-terminal domain (NTD) loops that are divergent both in sequence and in length from those of other sarbecoviruses ( 23 see also Fig. S1 in the supplemental material). To this end, we focused on comparing SARS-CoV-2 S with the S proteins of related sarbecoviruses. Our broad aims were to identify those consequential changes that alter the dynamics of virus-cell entry and infection. Numerous substitutions and deletions have been identified in the S proteins of viruses associated with the COVID19 pandemic ( 21, 22). Pre- and postfusion S protein structures ( 15, 16), structural intermediates on the refolding pathway ( 13, 17), and adaptive variations impacting the refolding process ( 18 – 20) indicate that these cell entry dynamics are under powerful selective forces, potentially influencing CoV transmissibility. Binding reorients S1 relative to virion-proximal S2 portions ( 11, 12), allowing S2 to extend, capture cell membranes via hydrophobic fusion peptides, and then pull cell and virus membranes into proximity, through a refolding process that ends in membrane fusion and stable “postfusion” helical bundles ( 13, 14). Multidomain S1 portions that are distal from the virion envelopes bind to attachment factors and bona fide protein receptors ( 9, 10). These functions are executed by several S protein domains that are arranged into metastable “prefusion” configurations. The S proteins are complex ∼500-kDa homo-trimers, operating as molecular machines that bind viruses to target cells and catalyze the fusion of virus and cell membranes. Intercellular and human-to-human transmission requires S proteins, as they direct virus entry into oro-nasal, airway, and alveolar epithelial cells ( 6 – 8). The concerning SARS-CoV-2 variations are within the viral spike (S) proteins. These forces may selectively amplify SARS-CoV-2 variants of concern. Considerable hypervariability in the SARS-CoV-2 spike protein NTDs also appear to be driven by counterbalancing pressures for effective virus-cell entry and durable extracellular virus infectivity. ![]() These findings parallel those obtained decades ago, in which comparisons of murine coronavirus spike protein variants established inverse relationships between membrane fusion potential and virus stability. Yet, those NTD changes elevating receptor binding and membrane fusion also reduced interdomain associations, leaving spikes on virus-like particles susceptible to irreversible inactivation. This revealed a significant allosteric effect, in that changes within the NTDs can orient RBDs for effective virus-cell binding. Increased cell entry correlated with greater presentation of RBDs to ACE2 receptors. We identified NTD variations that increased SARS-CoV-2 spike protein-mediated membrane fusion and cell entry. Therefore, we constructed indels and substitutions within hypervariable NTD regions and used severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus-like particles and quantitative virus-cell entry assays to elucidate spike structures controlling this initial infection stage. The impact of this hypervariability on virus entry is often unclear, particularly with respect to sarbecovirus NTD variations. These changes are concentrated in the amino-terminal domains (NTDs) and the receptor-binding domains (RBDs) of complex modular spike protein trimers. Selective pressures drive adaptive changes in the coronavirus spike proteins directing virus-cell entry.
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