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; Mei Hong

doi:10.1021/jacs.2c00973

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pH- and Calcium-Dependent Aromatic Network in the SARS-CoV-2 Envelope Protein

Journal article

Peer reviewed

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, Vol.144(15), pp.6839-6850

04/20/2022

DOI: 10.1021/jacs.2c00973

PMCID: PMC9188436

PMID: 35380805

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https://www.ncbi.nlm.nih.gov/pmc/articles/9188436View

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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 C and F 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. F 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 Ca 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.

Calcium - metabolism

COVID-19

Humans

Hydrogen-Ion Concentration

Ions

Lipids

Protein Conformation

SARS-CoV-2

Water

Details

Title: Subtitle: pH- and Calcium-Dependent Aromatic Network in the SARS-CoV-2 Envelope Protein
Creators: João Medeiros-Silva - Massachusetts Institute of Technology
Noah H Somberg - Massachusetts Institute of Technology
Harrison K Wang - Massachusetts Institute of Technology
Matthew J McKay - Massachusetts Institute of Technology
Venkata S Mandala - Massachusetts Institute of Technology
Aurelio J Dregni - Massachusetts Institute of Technology
Mei Hong - Massachusetts Institute of Technology
Resource Type: Journal article
Publication Details: Journal of the American Chemical Society, Vol.144(15), pp.6839-6850
DOI: 10.1021/jacs.2c00973
PMID: 35380805
PMCID: PMC9188436
NLM abbreviation: J Am Chem Soc
ISSN: 0002-7863
eISSN: 1520-5126
Grant note: P41 GM132079 / NIGMS NIH HHS
Language: English
Date published: 04/20/2022
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9985112883102771

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