Strikingly Different Roles of SARS-CoV-2 Fusion Peptides Uncovered by Neutron Scattering

Santamaria, Andreas; Batchu, Krishna Chaithanya; Matsarskaia, Olga; Prévost, Sylvain; Russo, Daniela; Natali, Francesca; Seydel, Tilo; Hoffmann, Ingo; Laux, Valerie; Haertlein, Michael; Darwish, Tamim A.; Russell, Robert A.; Corucci, Giacomo; Fragneto, Giovanna; Maestro, Armando; Zaccai, Nathan R.

doi:10.1021/jacs.1c09856

Cited by 36 publications

(57 citation statements)

References 53 publications

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“…An analysis of information obtained from various neutron scattering techniques accessing membrane structure and dynamics from SARS-CoV-2 protein–host interactions revealed that molecular interactions during spike protein fusion peptide binding events could induce changes in membrane fluidity and rigidity where fusion peptide 1 increased rigidity while fusion peptide 2 reduced fluidity [ 436 ]. Other morphological changes induced by SARS-CoV-2 as a result of fusion events include modification of both lipid composition and membrane structure to produce non-lamellar cubic membranes that facilitate membrane fusion during viral infection [ 437 ].…”

Section: Melatonin Protects Mitochondria and Atp Production To Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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Section: Melatonin Protects Mitochondria and Atp Production To Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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“…To date, research surrounding the FD has either concentrated on the peptides activity at pH 5.0 or assessed the FP and FL independently. 14 , 21 , 23 , 24 Initially, both domains were found to contain some fusogenic properties in isolation, with the FP even displaying a preference for fusion at low pH. 21 Since then, it has been proven that the FP and FL act in a synergistic manner to exert a membrane perturbing effect that is greater than that witnessed when the two components were assessed independently.…”

Section: Discussionmentioning

confidence: 99%

Exploring the pH dependence of the SARS‐CoV‐2 complete fusion domain and the role of its unique structural features

Birtles

Lee

2022

Protein Science

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SARS-CoV-2 may enter target cells through the process of membrane fusion at either the plasma ($pH 7.4-7.0) or endosomal ($pH 6.5-5.0) membrane in order to deliver its genetic information. The fusion domain (FD) of the spike glycoprotein is responsible for initiating fusion and is thus integral to the viral life cycle. The FD of SARS-CoV-2 is unique in that it consists of two structurally distinctive regions referred to as the fusion peptide (FP) and the fusion loop (FL); yet the molecular mechanisms behind how this FD perturbs the membrane to initiate fusion remains unclear. In this study via solution NMR, we witnessed only a slight conformational change in the FD between pH 7.4 and pH 5.0, resulting in a minor elongation of helix 1. However, we found that the FD's ability to mediate membrane fusion has a large and significant pH dependence, with fusion events being more readily induced at low pH. Interestingly, a biphasic relationship between the environmental pH and fusogenicity was discovered, suggesting a preference for the FD to initiate fusion at the late endosomal membrane. Furthermore, the conserved disulfide bond and hydrophobic motif "LLF" were found to be critical for the function of the complete FD, with minimal activity witnessed when either was perturbed. In conclusion, these findings indicate that the SARS-CoV-2 FD preferably initiates fusion at a pH similar to the late endosome through a mechanism that heavily relies on the internal disulfide bond of the FL and hydrophobic LLF motif within the FP.

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“…However, the high surface-to-volume (or surface-to-mass) ratio of deposited particles leads to a situation in which inhaled particles induce stronger effects than those that are expected considering only the deposited mass, i.e., the acquired dose [42,55,57,65,115,116]. Therefore, the evaluation of the safety of inhaled particles must consider the role of several parameters, including the dimensions of the particulate material and its concentration, the particle molecular structure, and other physico-chemical properties (hydrophobicity and charge) [69,114,[117][118][119][120][121][122][123][124][125].…”

Section: Impact Of Inhaled Particle Deposition In Lung Surfactant Filmmentioning

confidence: 99%

Fluid Films as Models for Understanding the Impact of Inhaled Particles in Lung Surfactant Layers

Guzmán

2022

Coatings

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Pollution is currently a public health problem associated with different cardiovascular and respiratory diseases. These are commonly originated as a result of the pollutant transport to the alveolar cavity after their inhalation. Once pollutants enter the alveolar cavity, they are deposited on the lung surfactant (LS) film, altering their mechanical performance which increases the respiratory work and can induce a premature alveolar collapse. Furthermore, the interactions of pollutants with LS can induce the formation of an LS corona decorating the pollutant surface, favoring their penetration into the bloodstream and distribution along different organs. Therefore, it is necessary to understand the most fundamental aspects of the interaction of particulate pollutants with LS to mitigate their effects, and design therapeutic strategies. However, the use of animal models is often invasive, and requires a careful examination of different bioethics aspects. This makes it necessary to design in vitro models mimicking some physico-chemical aspects with relevance for LS performance, which can be done by exploiting the tools provided by the science and technology of interfaces to shed light on the most fundamental physico-chemical bases governing the interaction between LS and particulate matter. This review provides an updated perspective of the use of fluid films of LS models for shedding light on the potential impact of particulate matter in the performance of LS film. It should be noted that even though the used model systems cannot account for some physiological aspects, it is expected that the information contained in this review can contribute on the understanding of the potential toxicological effects of air pollution.

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Strikingly Different Roles of SARS-CoV-2 Fusion Peptides Uncovered by Neutron Scattering

Cited by 36 publications

References 53 publications

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Exploring the pH dependence of the SARS‐CoV‐2 complete fusion domain and the role of its unique structural features

Fluid Films as Models for Understanding the Impact of Inhaled Particles in Lung Surfactant Layers

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