A pH-dependent switch mediates conformational masking of SARS-CoV-2 spike

BioRxiv : the Preprint Server for Biology
Tongqing ZhouPeter D. Kwong

Abstract

SARS-CoV-2 has emerged as a global pathogen, sparking urgent vaccine development efforts with the trimeric spike. However, the inability of antibodies like CR3022, which binds a cryptic spike epitope with nanomolar affinity, to neutralize virus, suggests a spike-based means of neutralization escape. Here, we show the SARS-CoV-2 spike to have 10% the unfolding enthalpy of a globular protein at physiological pH, where it is recognized by antibodies like CR3022, and up to 10-times more unfolding enthalpy at endosomal pH, where it sheds such antibodies, suggesting that the spike evades potentially neutralizing antibody through a pH-dependent mechanism of conformational masking. To understand the compatibility of this mechanism with ACE2-receptor interactions, we carried out binding measurements and determined cryo-EM structures of the spike recognizing up to three ACE2 molecules at both physiological and endosomal pH. In the absence of ACE2, cryo-EM analyses indicated lower pH to reduce conformational heterogeneity. Single-receptor binding domain (RBD)-up conformations dominated at pH 5.5, resolving into a locked all-down conformation at lower pH through lowering of RBD and refolding of a pH-dependent switch. Notably, the emerging ...Continue Reading

Citations

Oct 22, 2020·Nature Chemical Biology·Colton J BrackenJames A. Wells
Dec 2, 2020·Biochemical Society Transactions·Dene R LittlerBenjamin S Gully
Oct 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Anum GlasgowJames A. Wells
Jan 13, 2021·Nature Communications·Jarek JuraszekJohannes P M Langedijk
Mar 28, 2021·European Journal of Clinical Pharmacology·Suzy HuijghebaertGuido Vanham
Jun 3, 2021·Journal of Xenobiotics·Khalid O AlfaroukStephan J Reshkin

Methods Mentioned

BETA
differential scanning calorimetry
isothermal titration calorimetry
surface plasmon resonance
biolayer interferometry

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