Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition.

Asor, Roi; Olerinyova, Anna; Burnap, Sean A; Kushwah, Manish S; Soltermann, Fabian; Rudden, Lucas S P; Hensen, Mario; Vasiljevic, Snežana; Brun, Juliane; Hill, Michelle; Chang, Liu; Dejnirattisai, Wanwisa; Supasa, Piyada; Mongkolsapaya, Juthathip; Zhou, Daming; Stuart, David I; Screaton, Gavin R; Degiacomi, Matteo T; Zitzmann, Nicole; Benesch, Justin L P; Struwe, Weston B; Kukura, Philipp

Abstract

Cellular processes are controlled by the thermodynamics of the underlying biomolecular interactions. Frequently, structural investigations use one monomeric binding partner, while ensemble measurements of binding affinities generally yield one affinity representative of a 1:1 interaction, despite the majority of the proteome consisting of oligomeric proteins. For example, viral entry and inhibition in SARS-CoV-2 involve a trimeric spike surface protein, a dimeric angiotensin-converting enzyme 2 (ACE2) cell-surface receptor and dimeric antibodies. Here, we reveal that cooperativity correlates with infectivity and inhibition as opposed to 1:1 binding strength. We show that ACE2 oligomerizes spike more strongly for more infectious variants, while exhibiting weaker 1:1 affinity. Furthermore, we find that antibodies use induced oligomerization both as a primary inhibition mechanism and to enhance the effects of receptor-site blocking. Our results suggest that naive affinity measurements are poor predictors of potency, and introduce an antibody-based inhibition mechanism for oligomeric targets. More generally, they point toward a much broader role of induced oligomerization in controlling biomolecular interactions.

Citation

Asor, R., Olerinyova, A., Burnap, S. A., Kushwah, M. S., Soltermann, F., Rudden, L. S. P., Hensen, M., Vasiljevic, S., Brun, J., Hill, M., Chang, L., Dejnirattisai, W., Supasa, P., Mongkolsapaya, J., Zhou, D., Stuart, D. I., Screaton, G. R., Degiacomi, M. T., Zitzmann, N., Benesch, J. L. P., …Kukura, P. (2024). Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition. Proceedings of the National Academy of Sciences, 121(40), Article e2403260121. https://doi.org/10.1073/pnas.2403260121

• Journal Article Type: Article
• Acceptance Date: Jun 28, 2024
• Online Publication Date: Sep 19, 2024
• Publication Date: Sep 19, 2024
• Deposit Date: Oct 11, 2024
• Publicly Available Date: Oct 11, 2024
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 121
• Issue: 40
• Article Number: e2403260121
• DOI: https://doi.org/10.1073/pnas.2403260121
• Keywords: Antibodies, Viral - immunology - metabolism, receptor oligomerization, SARS-CoV-2 - metabolism, Humans, mass photometry, Spike Glycoprotein, Coronavirus - metabolism - chemistry, SARS-CoV-2, Thermodynamics, Angiotensin-Converting Enzyme 2 - metabolism - c
• Public URL: https://durham-repository.worktribe.com/output/2948197