Cryo-EM Structures Delineate a pH-Dependent Switch that Mediates Endosomal Positioning of SARS-CoV-2 Spike Receptor-Binding Domains
Adam S. Olia,
Phinikoula S. Katsamba,
Jared M. Sampson,
Jeffrey C Boyington,
Richard A. Friesner,
David D Ho,
John R Mascola,
Peter D Kwong
Posted 04 Jul 2020
bioRxiv DOI: 10.1101/2020.07.04.187989
Posted 04 Jul 2020
The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the ACE2 receptor and to facilitate virus entry. Antibodies can engage RBD but some, such as CR3022, fail to inhibit entry despite nanomolar spike affinity. Here we show the SARS-CoV-2 spike to have low unfolding enthalpy at serological pH and up to 10-times more unfolding enthalpy at endosomal pH, where we observe significantly reduced CR3022 affinity. Cryo-EM structures –at serological and endosomal pH– delineated spike recognition of up to three ACE2 molecules, revealing RBD to freely adopt the ‘up’ conformation. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a locked all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning and spike shedding of antibodies like CR3022. An endosomal mechanism involving spike-conformational change can thus facilitate immune evasion from RBD-‘up’-recognizing antibody. Highlights ### Competing Interest Statement The authors have declared no competing interest.
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