tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2024 Oct;121(40):e2403260121.
doi: 10.1073/pnas.2403260121. Epub 2024 Sep 19. Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition
Roi Asor[SUP] 1 2 [/SUP], Anna Olerinyova[SUP] 1 2 [/SUP], Sean A Burnap[SUP] 2 3 [/SUP], Manish S Kushwah[SUP] 1 2 [/SUP], Fabian Soltermann[SUP] 1 2 [/SUP], Lucas S P Rudden[SUP] 4 [/SUP], Mario Hensen[SUP] 2 3 [/SUP], Snežana Vasiljevic[SUP] 2 3 [/SUP], Juliane Brun[SUP] 2 3 [/SUP], Michelle Hill[SUP] 2 3 [/SUP], Liu Chang[SUP] 5 6 [/SUP], Wanwisa Dejnirattisai[SUP] 5 7 [/SUP], Piyada Supasa[SUP] 5 [/SUP], Juthathip Mongkolsapaya[SUP] 5 6 [/SUP], Daming Zhou[SUP] 8 [/SUP], David I Stuart[SUP] 8 9 [/SUP], Gavin R Screaton[SUP] 5 10 [/SUP], Matteo T Degiacomi[SUP] 4 [/SUP], Nicole Zitzmann[SUP] 2 3 [/SUP], Justin L P Benesch[SUP] 1 2 [/SUP], Weston B Struwe[SUP] 2 3 [/SUP], Philipp Kukura[SUP] 1 2 [/SUP]
Affiliations
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.
Keywords: SARS-CoV-2; avidity-based neutralization potency; label-free single-molecule tracking; mass photometry; receptor oligomerization.
. 2024 Oct;121(40):e2403260121.
doi: 10.1073/pnas.2403260121. Epub 2024 Sep 19. Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition
Roi Asor[SUP] 1 2 [/SUP], Anna Olerinyova[SUP] 1 2 [/SUP], Sean A Burnap[SUP] 2 3 [/SUP], Manish S Kushwah[SUP] 1 2 [/SUP], Fabian Soltermann[SUP] 1 2 [/SUP], Lucas S P Rudden[SUP] 4 [/SUP], Mario Hensen[SUP] 2 3 [/SUP], Snežana Vasiljevic[SUP] 2 3 [/SUP], Juliane Brun[SUP] 2 3 [/SUP], Michelle Hill[SUP] 2 3 [/SUP], Liu Chang[SUP] 5 6 [/SUP], Wanwisa Dejnirattisai[SUP] 5 7 [/SUP], Piyada Supasa[SUP] 5 [/SUP], Juthathip Mongkolsapaya[SUP] 5 6 [/SUP], Daming Zhou[SUP] 8 [/SUP], David I Stuart[SUP] 8 9 [/SUP], Gavin R Screaton[SUP] 5 10 [/SUP], Matteo T Degiacomi[SUP] 4 [/SUP], Nicole Zitzmann[SUP] 2 3 [/SUP], Justin L P Benesch[SUP] 1 2 [/SUP], Weston B Struwe[SUP] 2 3 [/SUP], Philipp Kukura[SUP] 1 2 [/SUP]
Affiliations
- PMID: 39298475
- DOI: 10.1073/pnas.2403260121
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.
Keywords: SARS-CoV-2; avidity-based neutralization potency; label-free single-molecule tracking; mass photometry; receptor oligomerization.