Key result
The SARS-CoV-2 fusion peptide induces greater membrane ordering than the SARS-CoV fusion peptide, with a highly specific dependence on calcium ions that promotes viral entry.
Why the study?
Coronaviruses entry into host cells is mediated by the spike protein, and the membrane ordering effect of the identified SARS-CoV-2 fusion peptide needed evaluation.
The SARS-CoV-2 fusion peptide exhibits greater membrane perturbating effects and stronger, highly specific calcium dependence compared to SARS-CoV, suggesting calcium interaction as a potential therapeutic target for blocking viral entry.
May identify calcium as entry target in SARS-CoV-2; leaves open in vivo translation and therapeutic viability.
Coronaviruses are a major infectious disease threat, and include the zoonotic-origin human pathogens SARS-CoV-2, SARS-CoV, and MERS-CoV (SARS-2, SARS-1, and MERS). Entry of coronaviruses into host cells is mediated by the spike (S) protein. In our previous ESR studies, the local membrane ordering effect of the fusion peptide (FP) of various viral glycoproteins including the S of SARS-1 and MERS has been consistently observed. We previously determined that the sequence immediately downstream from the S2’ cleavage site is the bona fide SARS-1 FP. In this study, we used sequence alignment to identify the SARS-2 FP, and studied its membrane ordering effect. Although there are only three residue difference, SARS-2 FP induces even greater membrane ordering than SARS-1 FP, possibly due to its greater hydrophobicity. This may be a reason that SARS-2 is better able to infect host cells. In addition, the membrane binding enthalpy for SARS-2 is greater. Both the membrane ordering of SARS-2 and SARS-1 FPs are dependent on Ca 2+ , but that of SARS-2 shows a greater response to the presence of Ca 2+ . Both FPs bind two Ca 2+ ions as does SARS-1 FP, but the two Ca 2+ binding sites of SARS-2 exhibit greater cooperativity. This Ca 2+ dependence by the SARS-2 FP is very ion-specific. These results show that Ca 2+ is an important regulator that interacts with the SARS-2 FP and thus plays a significant role in SARS-2 viral entry. This could lead to therapeutic solutions that either target the FP-calcium interaction or block the Ca 2+ channel.
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Lai et al. (2021) studied SARS-CoV-2 viral entry mechanism. SARS-CoV-2 Fusion Peptide vs. SARS-CoV Fusion Peptide was evaluated on Membrane ordering effect (order parameter S0). The SARS-CoV-2 fusion peptide induces greater membrane ordering than the SARS-CoV fusion peptide, with a highly specific dependence on calcium ions that promotes viral entry.
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