SARS-CoV and SARS-CoV-2 cell entry begins when spike
glycoprotein
(S) docks with the human ACE2 (hACE2) receptor. While the two coronaviruses
share a common receptor and architecture of S, they exhibit differences
in interactions with hACE2 as well as differences in proteolytic processing
of S that trigger the fusion machine. Understanding how those differences
impact S activation is key to understand its function and viral pathogenesis.
Here, we investigate hACE2-induced activation in SARS-CoV and SARS-CoV-2
S using hydrogen/deuterium-exchange mass spectrometry (HDX-MS).
HDX-MS revealed differences in dynamics in unbound S, including open/closed
conformational switching and D614G-induced S stability. Upon hACE2
binding, notable differences in transduction of allosteric changes
were observed extending from the receptor binding domain to regions
proximal to proteolytic cleavage sites and the fusion peptide. Furthermore,
we report that dimeric hACE2, the native oligomeric form of the receptor,
does not lead to any more pronounced structural effect in S compared
to saturated monomeric hACE2 binding. These experiments provide mechanistic
insights into receptor-induced activation ofSarbecovirusspike proteins.