Furin cleavage-site (CS) present between the S1/S2 junction in SARS-CoV2 spike (S) protein is critical to drive the fusion of SARS-CoV2 with the host cell. SARS-CoV2 falls in the sarbecovirus lineage that doesn’t comprise of furin CS and therefore makes its origin enigmatic. The available wild-type (Wt) SARS-CoV2 S protein with PDB ID: 6yvb lacks a stretch of amino acid including furin CS as well. All investigators till date have shown this stretch existing in the form of a loop. We are for the first time reporting that this stretch comprises of 14 amino acid residues (677QTNSPRRARSVASQ689), forming an antiparallel β-sheet comprising of PRRAR furin CS. We observed the presence of this antiparallel β-sheet in MERS spike protein as well. While switching over from Wt. SARS-CoV2 with PRRAR furin CS to B.1.1.7 variant with HRRAR furin CS, we found 3% increase in the percentage content of β stands. Interestingly, we found that the change of B.1.1.7 to B.1.617 variant comprising of RRRAR furin CS shifted the percentage secondary structure back to that found in Wt. SARS-CoV2. We anticipate that this β-sheet is used as a docking site by host cell proteases to act on furin-CS. Additionally, we studied the interaction of modeled SARS-CoV2 S protein with transmembrane protease, serine 2 (TMPRSS2), and furin proteases, which clearly highlighted that these proteases exclusively uses furin CS located in β-sheet to cleave the SARS-CoV2 S protein at its S1/S2 junction.
SARS-CoV2 spike (S) protein has been well recognized for its ability to bind with the angiotensin-converting enzyme (ACE2) receptor on human and other model lung epithelial cells. The furin cleavage-site (CS) present between the S1/S2 junction in SARS-CoV2 S protein is critical to drive the fusion between the SARS-CoV2 main body with the host cell. The available S protein structure lacks a stretch of amino acid including the furin CS as well. The majority of investigators have reported the presence of a loop harboring this patch. We are for the first time reporting this patch comprises of 14 amino acid residues (677QTNSPRRARSVASQ689) that form an antiparallel β-sheet comprising of PRRAR furin polybasic CS. We anticipate that this β-sheet is used as a scaffold by proteases to act on furin-CS in SARS-CoV2 S protein. Additionally, we studied the interaction of modeled SARS-CoV2 S protein with transmembrane protease, serine 2 (TMPRSS2), and furin proteases that accentuated that these proteases use furin CS sequence (PRRAR) located in β-sheet of our modeled SARS-CoV2 S protein to cleave the SARS-CoV2 S protein at S1/S2 junction.
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