Structure of a Conserved Golgi Complex-targeting Signal in Coronavirus Envelope Proteins

Li, Yan; Surya, Wahyu; Claudine, Stephanie; Torres, Jaume

doi:10.1074/jbc.m114.560094

Cited by 124 publications

(201 citation statements)

References 74 publications

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“…Surya et al SARS-CoV E. 48 This α-helical conformation is consistent with circular dichroism and Fourier transform infrared spectroscopy data. 47 Overall, this discrepancy may point to the existence of a frustrated structure poised for conformational change in this part of the molecule.…”

supporting

confidence: 66%

“…This narrower luminal end is also where inhibitors were found to bind. 48,84 This funnel-like architecture has also been observed in other viroporins, for example, influenza M2 protein 5 and HCV p7. 50 Both viroporins delay apoptosis in infected cells, which may help evade host inflammatory responses and the premature death of the host cells.…”

Section: Resultsmentioning

confidence: 83%

“…SARS-CoV E channel activity is inhibited partially by HMA in the K d ∼10 µM range. 51,52 The interaction of this drug with the channel has been mapped to residues located at the N-and C-terminal ends of the TM region 48,19 ( Figure 4A and B). Affected residues at the N-terminal end include the conserved polar residue Asn-15, suggesting HMA binding to the N-terminal, luminal facing, end of the channel.…”

Section: Channel Activity Inhibitors Of Sars-cov E and Rsv Sh Proteinsmentioning

confidence: 99%

“…54 A truncated form of SARS-CoV E (8-65) in DPhPC (diphytanoylphosphatidylcholine) showed a conductance of 0.39±0.02 nS. 48 For comparison, synthetic fulllength SARS-CoV E and E (7-38) produced single channel conductances of 0.19±0.06 nS and 0.18±0.12 nS in 1 M NaCl, 53 respectively. The lower conductance observed in synthetic samples may be due to extraneous modifications or impurities resulting from exposure to harsh chemicals.…”

mentioning

confidence: 99%

“…47,48 Current data suggest that disulfide bonds, or the presence of juxtamembrane cysteines, are not required for oligomerization for TGEV E, 24 IBV E, 47 MHV E, 30 or SARS E. 48 A more detailed study of the TM structure of SARS-CoV E was obtained from solution NMR of a synthetic isotopically labeled E in dodecylphosphocholine (DPC) detergent micelles. 19 A model of the pentamer was derived from intermonomeric Nuclear Overhauser effects and paramagnetic relaxation enhancement data, confirming the TM helix orientations reported previously.…”

mentioning

confidence: 99%

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Pentameric viral ion channels: from structure to function

Surya¹,

Li²,

Torres³

2014

JRLCR

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A family of small polypeptides in many virus types associate to form oligomers and have channel activity. These proteins have been referred to as viroporins or virochannels and are increasingly recognized as important virulence factors and potential drug targets. In this review, we focus on two of the viroporins that have been studied in more detail from a structural and functional point of view. One is the 76-residue envelope (E) protein found in coronaviruses (CoVs) that causes the severe acute respiratory syndrome (SARS). The other is the 65-residue small hydrophobic (SH) protein found in a paramyxovirus, the respiratory syncytial virus (RSV). RSV SH and SARS-CoV E proteins are short polypeptides with a single transmembrane domain. In both cases, the presence of the viroporin has a protective effect on cells, preventing early apoptosis, but it leads to increased virulence in infected animal models. Both viroporins form homopentameric oligomers that show channel activity with no or low selectivity. The role of channel activity is still unclear, but associations have been made to facilitation of the egress of the virus by modification of the secretory pathway, and contributions to inflammation. SARS-CoV E protein has a cytoplasmically oriented C-terminus and a lumenal N-terminus, whereas the opposite orientation is found in RSV SH protein. Despite this opposite topology, nuclear magnetic resonance (NMR)-based structural models of these two channels show a similar champagne flute shape, with the wider opening facing the cytoplasmic side. Good channel inhibitors are lacking, but those found seem to have a preference for the narrow end of the channel. Availability of good inhibitors will help reveal the specific role of these channels in the life cycle of these viruses.

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supporting

confidence: 66%

Section: Resultsmentioning

confidence: 83%

Section: Channel Activity Inhibitors Of Sars-cov E and Rsv Sh Proteinsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pentameric viral ion channels: from structure to function

Surya¹,

Li²,

Torres³

2014

JRLCR

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Characterization of the SARS‐CoV‐2 E Protein: Sequence, Structure, Viroporin, and Inhibitors

et al. 2021

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The COVID-19 epidemic is one of the most influential epidemics in history. Understanding the impact of coronaviruses (CoVs) on host cells is very important for disease treatment. The SARS-CoV-2 envelope (E) protein is a small structural protein involved in many aspects of the viral life cycle. The E protein promotes the packaging and reproduction of the virus, and deletion of this protein weakens or even abolishes the virulence. This review aims to establish new knowledge by combining recent advances in the study of the SARS-CoV-2 E protein and by comparing it with the SARS-CoV E protein. The E protein amino acid sequence, structure, self-assembly characteristics, viroporin mechanisms and inhibitors are summarized and analyzed herein. Although the mechanisms of the SARS-CoV-2 and SARS-CoV E proteins are similar in many respects, specific studies on the SARS-CoV-2 E protein, for both monomers and oligomers, are still lacking. A comprehensive understanding of this protein should prompt further studies on the design and characterization of effective targeted therapeutic measures.

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Hexamethylene amiloride binds the SARS‐CoV‐2 envelope protein at the protein–lipid interface

Somberg,

Medeiros‐Silva,

et al. 2023

Protein Science

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The SARS‐CoV‐2 envelope (E) protein forms a five‐helix bundle in lipid bilayers whose cation‐conducting activity is associated with the inflammatory response and respiratory distress symptoms of COVID‐19. E channel activity is inhibited by the drug 5‐(N,N‐hexamethylene) amiloride (HMA). However, the binding site of HMA in E has not been determined. Here we use solid‐state NMR to measure distances between HMA and the E transmembrane domain (ETM) in lipid bilayers. 13C, 15N‐labeled HMA is combined with fluorinated or 13C‐labeled ETM. Conversely, fluorinated HMA is combined with 13C, 15N‐labeled ETM. These orthogonal isotopic labeling patterns allow us to conduct dipolar recoupling NMR experiments to determine the HMA binding stoichiometry to ETM as well as HMA‐protein distances. We find that HMA binds ETM with a stoichiometry of one drug per pentamer. Unexpectedly, the bound HMA is not centrally located within the channel pore, but lies on the lipid‐facing surface in the middle of the TM domain. This result suggests that HMA may inhibit the E channel activity by interfering with the gating function of an aromatic network. These distance data are obtained under much lower drug concentrations than in previous chemical shift data, which showed the largest perturbation for N‐terminal residues. This difference suggests that HMA has higher affinity for the protein‐lipid interface than the channel pore, which gives insight into the inhibition mechanism of HMA for SARS‐CoV‐2 E.This article is protected by copyright. All rights reserved.

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Structure of a Conserved Golgi Complex-targeting Signal in Coronavirus Envelope Proteins

Cited by 124 publications

References 74 publications

Pentameric viral ion channels: from structure to function

Pentameric viral ion channels: from structure to function

Characterization of the SARS‐CoV‐2 E Protein: Sequence, Structure, Viroporin, and Inhibitors

Hexamethylene amiloride binds the SARS‐CoV‐2 envelope protein at the protein–lipid interface

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