Zhang Qingrong, Rosa Raissa S L, Ray Ankita, Durlet Kimberley, Dorrazehi Gol Mohammad, Bernardi Rafael C, Alsteens David
Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, Croix du sud 4-5, L7.07.07, Louvain-la-Neuve, Belgium.
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL, USA.
Nat Commun. 2025 Jan 2;16(1):6. doi: 10.1038/s41467-024-55358-9.
The SARS-CoV-2 spike protein's membrane-binding domain bridges the viral and host cell membrane, a critical step in triggering membrane fusion. Here, we investigate how the SARS-CoV-2 spike protein interacts with host cell membranes, focusing on a membrane-binding peptide (MBP) located near the TMPRSS2 cleavage site. Through in vitro and computational studies, we examine both primed (TMPRSS2-cleaved) and unprimed versions of the MBP, as well as the influence of its conserved disulfide bridge on membrane binding. Our results show that the MBP preferentially associates with cholesterol-rich membranes, and we find that cholesterol depletion significantly reduces viral infectivity. Furthermore, we observe that the disulfide bridge stabilizes the MBP's interaction with the membrane, suggesting a structural role in viral entry. Together, these findings highlight the importance of membrane composition and peptide structure in SARS-CoV-2 infectivity and suggest that targeting the disulfide bridge could provide a therapeutic strategy against infection.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的膜结合结构域连接病毒膜和宿主细胞膜，这是触发膜融合的关键步骤。在此，我们研究SARS-CoV-2刺突蛋白如何与宿主细胞膜相互作用，重点关注位于跨膜丝氨酸蛋白酶2（TMPRSS2）切割位点附近的膜结合肽（MBP）。通过体外和计算研究，我们检测了MBP的引发（TMPRSS2切割）和未引发版本，以及其保守二硫键对膜结合的影响。我们的结果表明，MBP优先与富含胆固醇的膜结合，并且我们发现胆固醇耗竭显著降低病毒感染性。此外，我们观察到二硫键稳定了MBP与膜的相互作用，表明其在病毒进入过程中具有结构作用。总之，这些发现突出了膜组成和肽结构在SARS-CoV-2感染性中的重要性，并表明靶向二硫键可能提供一种抗感染的治疗策略。
