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

Author(s)

Mansor Basso, Luis Guilherme ^{[1, 2]} ; Zeraik, Ana Eliza ^{[3, 4]} ; Felizatti, Ana Paula ^{[4, 5]} ; Costa-Filho, Antonio Jose ^[2]

Affiliation

^[1] Univ Estadual Norte Fluminense, Ctr Ciencia & Tecnol, Lab Ciencias Fis, Ave Alberto Lamego 2000, BR-28013602 Campos Dos Goytacazes, RJ - Brazil

^[2] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Fis, Lab Biofis Mol, Ave Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil

^[3] Univ Estadual Norte Fluminense, Ctr Biociencias & Biotecnol, Lab Quim & Funcao Proteinas & Peptideos, Ave Alberto Lamego 2000, BR-28013602 Campos Dos Goytacazes, RJ - Brazil

^[4] Univ Sao Paulo, Inst Fis Sao Carlos, Grp Biofis & Biol Estrutural Sergio Mascarenhas, Ave Trabalhador Sao Carlense 400, Sao Carlos, SP - Brazil

^[5] Univ Fed Sao Carlos, Ctr Ciencias Exatas & Tecnol, Dept Quim, Lab Prod Nat, Rod Washington Luiz, Km 235, BR-13565905 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES; v. 1863, n. 11 NOV 1 2021.
• Web of Science Citations: 0

Abstract

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 a-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, Ca2+ 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. (AU)

• FAPESP's process: 08/57910-0 - National Institute of Structural Biotechnology and Medicinal Chemistry in Infectious Diseases
• Grantee: Richard Charles Garratt
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/50366-7 - Resolving mechanistic details of peptide transport across membranes using crystallographic and non-crystallographic structural biology approaches
• Grantee: Antonio José da Costa Filho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/00206-0 - Structure and function of SARS-CoV spike glycoprotein fusion peptides
• Grantee: Luís Guilherme Mansor Basso
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/18390-5 - Electron magnetic resonance in molecular biophysics: new and old looks to new and old problems
• Grantee: Antonio José da Costa Filho
• Support Opportunities: Regular Research Grants