Polar Networks Mediate Ion Conduction of the SARS-CoV-2 Envelope Protein
Name
nihms-2090419.pdf
Description
Accepted version
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2.6 MB
Format
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Checksum (MD5)
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Author(s)
Medeiros-Silva, João
Pankratova, Yanina
Sučec, Iva
Dregni, Aurelio J
Hong, Mei
Date Issued
December 27, 2024
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Polar Networks Mediate Ion Conduction of the SARS-CoV-2 Envelope Protein. João Medeiros-Silva, Yanina Pankratova, Iva Sučec, Aurelio J. Dregni, and Mei Hong. Journal of the American Chemical Society 2025 147 (1), 746-757.
Version
Author's final manuscript
Abstract
The SARS-CoV-2 E protein conducts cations across the cell membrane to cause pathogenicity to infected cells. The high-resolution structures of the E transmembrane domain (ETM) in the closed state at neutral pH and in the open state at acidic pH have been determined. However, the ion conduction mechanism remains elusive. Here, we use solid-state NMR spectroscopy to investigate the side chain structure, dynamics, and interactions of five polar residues at the N-terminal entrance of the channel and three polar residues at the C-terminal end. The chemical shifts of the N-terminal Glu8 reveal that the Glu side chain interacts with protons, Ca2+ and two neighboring Thr residues, and adopts distinct motionally averaged conformational ensembles. These polar interactions are sensitive to the presence of negatively charged lipids in the membrane. A T9I mutation, prevalent in the Omicron variants of SARS-CoV-2 E, perturbs these interactions and partially immobilizes the N-terminal segment. Deeper into the channel, two polar residues, Asn15 and Ser16, form interhelical hydrogen bonds in the closed state but become separated by water molecules in the open state. This is manifested by Asn15-Ser16 correlation signals at neutral pH and the loss of these correlations and the appearance of water cross peaks with Ser16 at acidic pH in the presence of Ca2+. Finally, the guanidinium side chain of the C-terminal Arg38 undergoes fast reorientations in the closed state but becomes more restricted in the open state. These results provide evidence for a dynamic and hydrogen-bonded N-terminal polar network that recruits and relays protons and Ca2+ in a lipid-dependent manner. Once inside, the ions permeate past the hydrophobic middle of the transmembrane domain with the help of enhanced hydrophilicity of the C-terminal channel lumen due to the insertion of the Arg38 side chain into the pore.
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DOI of Published Version
https://doi.org/10.1021/jacs.4c13229
