Controlling the SARS-CoV-2 Spike Glycoprotein Conformation

By R. Henderson, R. Edwards, K. Mansouri, Katarzyna Janowska, V. Stalls, S. Gobeil, Megan Kopp, A. Hsu, M. Borgnia, R. Parks and 2 more. 2020

236 citations recorded by the source corpus.

The coronavirus (CoV) viral host cell fusion spike (S) protein is the primary immunogenic target for virus neutralization and the current focus of many vaccine design efforts. The highly flexible S-protein, with its mobile domains, presents a moving target to the immune system. Here, to better understand S-protein mobility, we implemented a structure-based vector analysis of available β-CoV S-protein structures. We found that despite overall similarity in domain organization, different β-CoV strains display distinct S-protein configurations. Based on this analysis, we developed two soluble ectodomain constructs in which the highly immunogenic and mobile receptor binding domain (RBD) is locked in either the all-RBDs ‘down’ position or is induced to display a previously unobserved in SARS-CoV-2 2-RBDs ‘up’ configuration. These results demonstrate that the conformation of the S-protein can be controlled via rational design and provide a framework for the development of engineered coronavirus spike proteins for vaccine applications.

Subfields: Infectious Diseases, Molecular Biology, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, positive): “Several reports of stabilized prefusion SARS-CoV-2 S variants provide promising antigens that can be used to test this hypothesis (Henderson et al., 2020; Hsieh et al., 2020; McCallum et al., 2020; Xiong et al., 2020).”
Molecular Architecture of the SARS-CoV-2 Virus (2020, background): “The “RBD down”, “one RBD up” and “two-RBD up” conformations have been observed in recombinantly expressed S proteins of SARS-CoV-2 (Henderson et al., 2020; Walls et al., 2020; Wrapp et al., 2020).”
Cold sensitivity of the SARS-CoV-2 spike ectodomain (2021, unknown): “We found that 2P S stored at 4 °C showed higher binding to antibody CR3022 and to receptor ACE-2, which both require an “up” RBD conformation for stable binding 1,9,12 , compared to freshly prepared protein.”