pH- and Calcium-Dependent Aromatic Network in the SARS-CoV-2 Envelope Protein
Name
nihms-1812063.pdf
Description
Accepted version
Size
2.31 MB
Format
Adobe PDF
Checksum (MD5)
042ad06a946679d8ffa7ed705cc12573
Author(s)
Medeiros-Silva, João
Somberg, Noah H
Wang, Harrison K
McKay, Matthew J
Mandala, Venkata S
Dregni, Aurelio J
Hong, Mei
Date Issued
April 5, 2022
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
pH- and Calcium-Dependent Aromatic Network in the SARS-CoV-2 Envelope Protein. João Medeiros-Silva, Noah H Somberg, Harrison K. Wang, Matthew J. McKay, Venkata S. Mandala, Aurelio J. Dregni, and Mei Hong. Journal of the American Chemical Society 2022 144 (15), 6839-6850.
Version
Author's final manuscript
Abstract
The envelope (E) protein of the SARS-CoV-2 virus is a membrane-bound viroporin that conducts cations across the endoplasmic reticulum Golgi intermediate compartment (ERGIC) membrane of the host cell to cause virus pathogenicity. The structure of the closed state of the E transmembrane (TM) domain, ETM, was recently determined using solid-state NMR spectroscopy. However, how the channel pore opens to mediate cation transport is unclear. Here, we use 13C and 19F solid-state NMR spectroscopy to investigate the conformation and dynamics of ETM at acidic pH and in the presence of calcium ions, which mimic the ERGIC and lysosomal environment experienced by the E protein in the cell. Acidic pH and calcium ions increased the conformational disorder of the N- and C-terminal residues and also increased the water accessibility of the protein, indicating that the pore lumen has become more spacious. ETM contains three regularly spaced phenylalanine (Phe) residues in the center of the peptide. 19F NMR spectra of para-fluorinated Phe20 and Phe26 indicate that both residues exhibit two sidechain conformations, which coexist within each channel. These two Phe conformations differ in their water accessibility, lipid contact, and dynamics. Channel opening by acidic pH and Ca2+ increases the population of the dynamic lipid-facing conformation. These results suggest an intricate aromatic network that regulates the opening of the ETM channel pore. This aromatic network may be a target for E inhibitors against SARS-CoV-2 and related coronaviruses.
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DOI of Published Version
https://doi.org/10.1021/jacs.2c00973
