TY - JOUR
AU - Asor, Roi
AU - Olerinyova, Anna
AU - Burnap, Sean A.
AU - Kushwah, Manish S.
AU - Soltermann, Fabian
AU - Rudden, Lucas S.P.
AU - Hensen, Mario
AU - Vasiljevic, Snežana
AU - Brun, Juliane
AU - Hill, Michelle
AU - Chang, Liu
AU - Dejnirattisai, Wanwisa
AU - Supasa, Piyada
AU - Mongkolsapaya, Juthathip
AU - Zhou, Daming
AU - Stuart, David I.
AU - Screaton, Gavin R.
AU - Degiacomi, Matteo T.
AU - Zitzmann, Nicole
AU - Benesch, Justin L.P.
AU - Struwe, Weston B.
AU - Kukura, Philipp
PY - 2024
DA - September
TI - Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition
JO - Proceedings of the National Academy of Sciences of the United States of America
VL - 121
IS - 40
DO - https://doi.org/10.5287/ora-1zppvdavr
AB - 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.
PB - National Academy of Sciences
UR - https://www.research.ed.ac.uk/en/publications/1ddc923c-cea4-449f-892d-e5b325b98a2e
KW - Coronavirus (COVID-19)
ER