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Unravelling the SARS-CoV-2 mechanism of entry into host cells is engaging the endeavours of researchers worldwide and, although angiotensin-converting enzyme 2 (ACE2) is recognised as the primary receptor, many issues remain to be investigated.1
Remarkably, the interaction between ACE2 and the spike (S) glycosylated protein of SARS-CoV-2 necessary for viral entry has been discovered by employing crystallography. S protein presents a receptor binding domain (RBD) and more specifically a receptor binding motif (RBM) which mediates the attachment to two virus-binding hotspots within ACE2 surface. The aminoacidic constitution of SARS-CoV-2 RBM is highly homologous to that of SARS-CoV but shows some differences, specifically a four-residue motif at 482–485 (Gly-Val-Glu-Gly) that confers more affinity for ACE2 resulting in a tight relation between the two molecules.2
However, S protein, a trimeric class I fusion protein, is maintained in a metastable prefusion conformation and the RBD is largely in a lying-down status, a receptor inaccessible condition, facilitating immune escape, that needs to pass through a massive reconfiguration to trigger the viral-cell fusion.3
Recent evidence demonstrated that other molecular strategies are exploited by SARS-CoV-2 to enter host cells, thus explaining its high infectivity. Interestingly, Shang et al reported the possible pre-activation of the virus by furin, acting in synergy with Transmembrane protease, serine 2 (TMPRSS2) and cathepsins.4
Furin is a member of the proprotein convertase family whose components mediate the regulation of different proteins. Furin is able to cleave different substrates, both endogenous and exogenous, as bacterial toxins and viral molecules; therefore, it is involved in many infectious diseases including those caused by coronavirus.5
FURIN expression is rather ubiquitary, but different isoform combinations can be found in human …
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