Post by Nadica (She/Her) on Aug 21, 2024 1:52:46 GMT
Structure and inhibition of SARS-CoV-2 spike refolding in membranes - Published Aug 15, 2024
Editor’s summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses a spike protein to bind to receptors on human cells. Cleavage of spike by a protease yields a fragment called S2 that is primed to initiate membrane fusion through a dramatic conformational change that has so far been difficult to visualize using structural techniques. Using virus-like particles decorated either with spike or the receptor, Grunst et al. collected cryo–electron tomography images of membrane-associated spike-receptor complexes and S2 undergoing refolding. The authors were able to solve a prehairpin structure in which S2 is inserted into the opposing membrane, and they mapped models from prior molecular dynamics simulations onto the tomography structures. Stem-helix–targeting antibodies bound near the head of the prehairpin complex, resulting in arrest of refolding and prevention of fusion of the adjacent membranes. —Michael A. Funk
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo–electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into S2 intermediates, which were captured at various stages of refolding. Pan-betacoronavirus neutralizing antibodies targeting the S2 stem-helix bound to and inhibited refolding of spike prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate the process of SARS-CoV-2 entry and reveal how pan-betacoronavirus S2-targeting antibodies neutralize infectivity by arresting prehairpin intermediates.
Editor’s summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses a spike protein to bind to receptors on human cells. Cleavage of spike by a protease yields a fragment called S2 that is primed to initiate membrane fusion through a dramatic conformational change that has so far been difficult to visualize using structural techniques. Using virus-like particles decorated either with spike or the receptor, Grunst et al. collected cryo–electron tomography images of membrane-associated spike-receptor complexes and S2 undergoing refolding. The authors were able to solve a prehairpin structure in which S2 is inserted into the opposing membrane, and they mapped models from prior molecular dynamics simulations onto the tomography structures. Stem-helix–targeting antibodies bound near the head of the prehairpin complex, resulting in arrest of refolding and prevention of fusion of the adjacent membranes. —Michael A. Funk
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo–electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into S2 intermediates, which were captured at various stages of refolding. Pan-betacoronavirus neutralizing antibodies targeting the S2 stem-helix bound to and inhibited refolding of spike prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate the process of SARS-CoV-2 entry and reveal how pan-betacoronavirus S2-targeting antibodies neutralize infectivity by arresting prehairpin intermediates.