# Comparison of Selected Characteristics of SARS-CoV-2, SARS-CoV, and HCoV-NL63
### Morphology, Structure, and Replication of SARS-CoV-2
#### 1.3.4 Spike Protein and the Function of TMPRSS2  
Significant similarity exists between SARS-CoV and SARS-CoV-2. The level of similarity in the genome sequence has been confirmed to be 79.5% [13]. The E protein has been found to be present in both. The E protein has been found to be essential for the ability of other coronavirus to cause disease. It is encoded by the subgenomic RNA (sgRNA), which is among the transcripts with the highest copy number. This may be due to structural differences in the spike of the S protein. Recognition of the host cell occurs through the S protein and its receptor by a virion. The SARS-CoV-2-binding domain is at the S1 domain at its N-terminus [8]. For SARS-CoV, it is also on the S1 domain, but at its C-terminal end [32]. The interaction between the S protein and its receptor is responsible for the species specificity and the tissue tropism of the virus. Many CoVs use peptidases as cellular receptors. ACE2 is specific for SARS-CoV and HCoV-NL63. The surface of RBD S1 uses 14 amino acids that recognize ACE2. Of the 14, 8 are strictly bound to SARS-CoV-2. This is different from MERS-CoV, which is recognized by the dipeptidyl peptidase 4 (DPP4) of the host cells [33]. Upon receptor binding, the proteolytic cleavage of coronavirus S proteins by host-cell-derived proteases is essential to permit fusion. The virus enters the cytosol of the host cell via an acid-dependent proteolytic cleavage of the S protein by cathepsin, a specific TMPRRS2, followed by the fusion of viral and cell membranes. SARS-CoV-2 has been shown to use the cell-surface serine protease TMPRSS2 for priming and entry, although endosomal cysteine proteases cathepsin B (CatB) and CatL can also assist in this process. S protein cleavage occurs at two sites within the S2 portion of the protein, with the first cleavage for separating the RBD and fusion domains of the S protein. [27]. The second cleavage results in binding of the fusion peptide. Subsequently, the plasma membrane overflows. The exposed S2 fusion peptide aids in the fusion of membranes and the subsequent endocytosis and release of the viral genome into the host cell [34]. In addition to ACE2 entry factors, such as cellular glycans and integrins, may impact the observed phenotypic differences of SARS-CoV and SARS-CoV-2. Viruses infect host cells by initially binding to the surfaces of the cells. There are many pathogens, including viruses and bacteria that have the ability to use integrins with different mechanisms for invading cells. As multifunctional heterodimeric cell-surface receptor molecules, integrins have been shown to usefully serve as entry receptors for a plethora of viruses. The most common of these motifs is the peptide sequence for binding integrins, RGD (Arg-Gly-Asp). Virus-integrin binding is shown to facilitate adhesion, cytoskeleton rearrangement, integrin activation [35]. Virus binding only ensures viral proximity to cells. The SARS-CoV-2 spike glycoprotein RGD lies in the receptor-binding domain (amino acids 319 to 541) [36]. In order to bind integrin, the RGD motif must be present at the surface of the protein. ACE2 binding induces conformational changes involving one of the receptor-binding domains of the trimer. After a confirmatory change, the ACE2 binding domain and the RGD region are exposed. This process is the step that kick-starts the whole cascade of events, resulting in the eventual internalization of the virus. A cellular process reminiscent of viral infection revealed an endocytosis mechanism by which the cell surface heparan sulfate (HS) facilitates receptor-mediated uptake of protein assemblies bearing excess positive charges Heparan sulfate facilitates spike-dependent viral entry [37]. These mechanisms of virus penetration into the host cell are similar in SARS-CoV-2, SARS-CoV, and HCoV-NL63. A detailed description of the molecular events in the penetration of a virus or cell may be helpful in the development of specific therapeutic approaches [26].