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Although the structure of the RBD_ACE2 complex has been well studied, its functional mechanism in membrane fusion is still not fully understood. Here, using an in vitro cell\u2013vesicle content\u2010mixing assay, it is found that the cleavage at the S2\u2019 site by thrombin (Thr) protease strongly accelerates membrane fusion, compared to that of cleavage at the S1\/S2 site by PreScission (3C) protease. Moreover, mutations at the RBD_ACE2 interface resulted in a positive correlation between binding affinity and fusion probability. In both the cell\u2013vesicle and cell\u2013cell fusion assays, by crosslinking two membranes via the neutravidin (NTV)_biotin interaction or complementary DNA strands, it is found that spike drives membrane fusion in the absence of ACE2, and a suitable distance between two membranes is critical for spike\u2010mediated membrane fusion. Finally, unsuitable membrane crosslinkers significantly inhibited the fusion probability in the presence of ACE2. Taken together, the results suggest that the RBD_ACE2 complex may act as a crosslinker to bridge the viral and cell membranes at a suitable distance, which is critical, but also substitutable for spike\u2010mediated SARS\u2010CoV\u20102 entry.<\/jats:p>","DOI":"10.1002\/advs.202301478","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T09:56:43Z","timestamp":1692611803000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Suitable Membrane Distance Regulated by the RBD_ACE2 Interaction is Critical for SARS\u2010CoV\u20102 Spike\u2010Mediated Viral Invasion"],"prefix":"10.1002","volume":"10","author":[{"given":"Mengdan","family":"Wu","sequence":"first","affiliation":[{"name":"National Clinical Research Center for Geriatrics State Key Laboratory of Biotherapy West China Hospital Sichuan University  Chengdu Sichuan 610041 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