Argyrou Mia, Pitsillou Eleni, Hung Andrew, El-Osta Assam, Karagiannis Tom C
Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Prahran, VIC 3004, Australia; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3010, Australia.
Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Prahran, VIC 3004, Australia; Epigenomic Medicine Laboratory at prospED Polytechnic, Carlton, VIC 3053, Australia; School of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia.
J Struct Biol. 2025 Jun 23;217(3):108229. doi: 10.1016/j.jsb.2025.108229.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogenic agent responsible for the coronavirus disease 2019 (COVID-19) pandemic, uses the trimeric spike protein to gain entry into the host cell. Structural studies have revealed that the spike protein is comprised of the S1 and S2 subunits. The S1 subunit of the spike protein contains the receptor-binding domain (RBD), which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor. The interaction between the RBD and ACE2 facilitates membrane fusion and host cell infection. The SARS-CoV-2 spike protein also contains a unique insertion of four amino acids that results in the 682-RRAR↓S-686 polybasic furin cleavage motif at the boundary of the S1 and S2 subunits. The furin cleavage motif contributes to the high infectivity and transmissibility of SARS-CoV-2. This review provides a comprehensive analysis of the molecular interactions of the spike protein, with a specific focus on the RBD and furin cleavage site. In addition to examining the binding characteristics with ACE2, the interactions with alternative receptors, such as neuropilin-1 (NRP1) and the nicotinic acetylcholine receptors (nAChRs) are highlighted. The ability of the spike protein to bind alternative receptors and host factors has been linked to the pathophysiology of COVID-19 and the persistence of symptoms in the post COVID-19 condition. Furthermore, we examine the impact of spike protein mutations on receptor affinity and disease severity. SARS-CoV-2 continues to evolve, with variants remaining an ongoing threat to public health. Understanding these molecular interactions is critical for the development of novel therapeutic interventions.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是导致2019冠状病毒病（COVID-19）大流行的病原体，它利用三聚体刺突蛋白进入宿主细胞。结构研究表明，刺突蛋白由S1和S2亚基组成。刺突蛋白的S1亚基包含受体结合域（RBD），该结构域与人类血管紧张素转换酶2（ACE2）受体结合。RBD与ACE2之间的相互作用促进膜融合和宿主细胞感染。SARS-CoV-2刺突蛋白还包含一个独特的四个氨基酸插入序列，该序列在S1和S2亚基的边界处形成682-RRAR↓S-686多碱性弗林蛋白酶切割基序。弗林蛋白酶切割基序有助于SARS-CoV-2的高感染性和传播性。本综述对刺突蛋白的分子相互作用进行了全面分析，特别关注RBD和弗林蛋白酶切割位点。除了研究与ACE2的结合特性外，还重点介绍了与其他受体的相互作用，如神经纤毛蛋白-1（NRP1）和烟碱型乙酰胆碱受体（nAChRs）。刺突蛋白与其他受体和宿主因子结合的能力与COVID-19的病理生理学以及COVID-19后症状的持续存在有关。此外，我们还研究了刺突蛋白突变对受体亲和力和疾病严重程度的影响。SARS-CoV-2持续进化，变异毒株仍然对公众健康构成持续威胁。了解这些分子相互作用对于开发新型治疗干预措施至关重要。
