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

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


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


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

differential scanning calorimetry
isothermal titration calorimetry
surface plasmon resonance
biolayer interferometry

Related Concepts

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.