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

• 成果类型: Article
• 署名作者: Asor, Roi; Olerinyova, Anna; Burnap, Sean A.; Kushwah, Manish S.; Soltermann, Fabian; Rudden, Lucas S. P.; Hensen, Mario; Vasiljevic, Snezana; 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
• 署名单位: University of Oxford; University of Oxford; University of Oxford; Durham University; University of Oxford; Wellcome Centre for Human Genetics; Chinese Academy of Medical Sciences - Peking Union Medical College; University of Oxford; Mahidol University; University of Oxford; Wellcome Centre for Human Genetics; Oxford University Hospitals NHS Foundation Trust
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10203
• DOI: 10.1073/pnas.2403260121
• 发表日期: 2024-10-01
• 关键词: virus; tracking; spike

摘要

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 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 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.