Ca2+-dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide

Khelashvili, George; Plante, Ambrose; Doktorova, Milka; Weinstein, Harel

doi:10.1016/j.bpj.2021.02.023

Cited by 63 publications

(96 citation statements)

References 51 publications

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“…RBD, receptor-binding domain (red); RBM, receptor-binding motif (yellow); SD1, subdomain 1; SD2, subdomain 2; FP, fusion peptide; S1, subunit 1 (blue); S2, subunit 2 (cyan). Since this field is still under global scientific investigation, a number of published sources, including the UniProt entry P0DTC2, were used to identify each domain along with their start and end locations[50][51][52][53][54][55][56][57][58][59].…”

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confidence: 99%

A Comprehensive Molecular Epidemiological Analysis of SARS-CoV-2 Infection in Cyprus from April 2020 to January 2021: Evidence of a Highly Polyphyletic and Evolving Epidemic

Chrysostomou

Vrancken

Koumbaris³

et al. 2021

Viruses

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The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in an extraordinary global public health crisis. In early 2020, Cyprus, among other European countries, was affected by the SARS-CoV-2 epidemic and adopted lockdown measures in March 2020 to limit the initial outbreak on the island. In this study, we performed a comprehensive retrospective molecular epidemiological analysis (genetic, phylogenetic, phylodynamic and phylogeographic analyses) of SARS-CoV-2 isolates in Cyprus from April 2020 to January 2021, covering the first ten months of the SARS-CoV-2 infection epidemic on the island. The primary aim of this study was to assess the transmissibility of SARS-CoV-2 lineages in Cyprus. Whole SARS-CoV-2 genomic sequences were generated from 596 clinical samples (nasopharyngeal swabs) obtained from community-based diagnostic testing centers and hospitalized patients. The phylogenetic analyses revealed a total of 34 different lineages in Cyprus, with B.1.258, B.1.1.29, B.1.177, B.1.2, B.1 and B.1.1.7 (designated a Variant of Concern 202012/01, VOC) being the most prevalent lineages on the island during the study period. Phylodynamic analysis showed a highly dynamic epidemic of SARS-CoV-2 infection, with three consecutive surges characterized by specific lineages (B.1.1.29 from April to June 2020; B.1.258 from September 2020 to January 2021; and B.1.1.7 from December 2020 to January 2021). Genetic analysis of whole SARS-CoV-2 genomic sequences of the aforementioned lineages revealed the presence of mutations within the S protein (L18F, ΔH69/V70, S898F, ΔY144, S162G, A222V, N439K, N501Y, A570D, D614G, P681H, S982A and D1118H) that confer higher transmissibility and/or antibody escape (immune evasion) upon the virus. Phylogeographic analysis indicated that the majority of imports and exports were to and from the United Kingdom (UK), although many other regions/countries were identified (southeastern Asia, southern Europe, eastern Europe, Germany, Italy, Brazil, Chile, the USA, Denmark, the Czech Republic, Slovenia, Finland, Switzerland and Pakistan). Taken together, these findings demonstrate that the SARS-CoV-2 infection epidemic in Cyprus is being maintained by a continuous influx of lineages from many countries, resulting in the establishment of an ever-evolving and polyphyletic virus on the island.

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confidence: 99%

A Comprehensive Molecular Epidemiological Analysis of SARS-CoV-2 Infection in Cyprus from April 2020 to January 2021: Evidence of a Highly Polyphyletic and Evolving Epidemic

Chrysostomou

Vrancken

Koumbaris³

et al. 2021

Viruses

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“…The FP2 peptide was the least effective in promoting membrane fusion and leakage in the conditions tested. However, it has been shown that the binding of Ca 2+ ions triggers FP2 membrane insertion and membrane order to the FP2 Asp and Glu residues [17] , [40] , [53] , and this binding is highly specific [42] . Therefore, it is tempting to investigate whether the low membrane fusion activity displayed by FP2H7 would be enhanced by Ca 2+ binding.…”

Section: Resultsmentioning

confidence: 99%

“…For the FP2H7-membrane fusion assays, we used LUVs comprised of 60% POPC, 20% of the anionic POPS, and 20% cholesterol (molar ratio), a lipid model membrane used in other fusion peptide studies [23] , [40] , [53] . The Ca 2+ -dependent SARS-CoV FP2H7 membrane insertion and membrane-ordering effect are virtually identical in POPS- and POPG-containing membranes [17] , [42] .…”

Section: Resultsmentioning

confidence: 99%

Membranotropic and biological activities of the membrane fusion peptides from SARS-CoV spike glycoprotein: The importance of the complete internal fusion peptide domain

Basso

Zeraik

Felizatti

et al. 2021

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Fusion peptides (FP) are prominent hydrophobic segments of viral fusion proteins that play critical roles in viral entry. FPs interact with and insert into the host lipid membranes, triggering conformational changes in the viral protein that leads to the viral-cell fusion. Multiple membrane-active domains from the severe acute respiratory syndrome (SARS) coronavirus (CoV) spike protein have been reported to act as the functional fusion peptide such as the peptide sequence located between the S1/S2 and S2’ cleavage sites (FP1), the S2’-adjacent fusion peptide domain (FP2), and the internal FP sequence (cIFP). Using a combined biophysical approach, we demonstrated that the α -helical coiled-coil-forming internal cIFP displayed the highest membrane fusion and permeabilizing activities along with membrane ordering effect in phosphatidylcholine (PC)/phosphatidylglycerol (PG) unilamellar vesicles compared to the other two N-proximal fusion peptide counterparts. While the FP1 sequence displayed intermediate membranotropic activities, the well-conserved FP2 peptide was substantially less effective in promoting fusion, leakage, and membrane ordering in PC/PG model membranes. Furthermore, Ca 2+ did not enhance the FP2-induced lipid mixing activity in PC/phosphatidylserine/cholesterol lipid membranes, despite its strong erythrocyte membrane perturbation. Nonetheless, we found that the three putative SARS-CoV membrane-active fusion peptide sequences here studied altered the physical properties of model and erythrocyte membranes to different extents. The importance of the distinct membranotropic and biological activities of all SARS-CoV fusion peptide domains and the pronounced effect of the internal fusion peptide sequence to the whole spike-mediated membrane fusion process are discussed.

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“…Moreover, calcium triggers protease-mediated membrane fusion activation of SARS-CoV-2 [ 46 ], while phosphorylated residues Y789 and T791 [ 47 ] near the N-terminus of FP may increase the negative charge and facilitate the accumulation of Ca 2+ ions. Besides, in the absence of Ca 2+ ions, membrane binding of FP will be reduced drastically [ 48 ], along with the fusion peptide binding two Ca 2+ ions whose binding sites show greater synergy [ 49 ]. Therefore, it can be seen that the combination of Ca 2+ ions with the FP can enhance penetration that changes the molecular organization of a specific area on the double layer to a greater extent.…”

Section: Introductionmentioning

confidence: 99%

COVID-19: the CaMKII-like system of S protein drives membrane fusion and induces syncytial multinucleated giant cells

Liu

2021

Immunol Res

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The SARS-CoV-2 S protein on the membrane of infected cells can promote receptor-dependent syncytia formation, relating to extensive tissue damage and lymphocyte elimination. In this case, it is challenging to obtain neutralizing antibodies and prevent them through antibodies effectively. Considering that, in the current study, structural domain search methods are adopted to analyze the SARS-CoV-2 S protein to find the fusion mechanism. The results show that after the EF-hand domain of S protein bound to calcium ions, S2 protein had CaMKII protein activities. Besides, the CaMKII_AD domain of S2 changed S2 conformation, facilitating the formation of HR1-HR2 six-helix bundles. Apart from that, the Ca 2+ -ATPase of S2 pumped calcium ions from the virus cytoplasm to help membrane fusion, while motor structures of S drove the CaATP_NAI and CaMKII_AD domains to extend to the outside and combined the viral membrane and the cell membrane, thus forming a calcium bridge. Furthermore, the phospholipid-flipping-ATPase released water, triggering lipid mixing and fusion and generating fusion pores. Then, motor structures promoted fusion pore extension, followed by the cytoplasmic contents of the virus being discharged into the cell cytoplasm. After that, the membrane of the virus slid onto the cell membrane along the flowing membrane on the gap of the three CaATP_NAI. At last, the HR1-HR2 hexamer would fall into the cytoplasm or stay on the cell membrane. Therefore, the CaMKII_like system of S protein facilitated membrane fusion for further inducing syncytial multinucleated giant cells.

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Ca2+-dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide

Cited by 63 publications

References 51 publications

A Comprehensive Molecular Epidemiological Analysis of SARS-CoV-2 Infection in Cyprus from April 2020 to January 2021: Evidence of a Highly Polyphyletic and Evolving Epidemic

A Comprehensive Molecular Epidemiological Analysis of SARS-CoV-2 Infection in Cyprus from April 2020 to January 2021: Evidence of a Highly Polyphyletic and Evolving Epidemic

Membranotropic and biological activities of the membrane fusion peptides from SARS-CoV spike glycoprotein: The importance of the complete internal fusion peptide domain

COVID-19: the CaMKII-like system of S protein drives membrane fusion and induces syncytial multinucleated giant cells

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