Abstract
The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680SPRRAR↓SV687 forming a cleavage motif RxxR for furin-like enzymes at the boundary of S1/S2 subunits. Cleavage at S1/S2 is important for efficient viral entry into target cells. The insertion is absent in other CoV-s of the same clade, including SARS-CoV1 that caused the 2003 outbreak. However, an analogous cleavage motif was present at S1/S2 of the Spike protein of the more distant Middle East Respiratory Syndrome coronavirus MERS-CoV. We show that a crucial third arginine at the left middle position, comprising a motif RRxR is required for furin recognition in vitro, while the general motif RxxR in common with MERS-CoV is not sufficient for cleavage. Further, we describe a surprising finding that the two serines at the edges of the insert SPRRAR↓SV can be efficiently phosphorylated by proline-directed and basophilic protein kinases. Both phosphorylations switch off furin’s ability to cleave the site. Although phospho-regulation of secreted proteins is still poorly understood, further studies, supported by a recent report of ten in vivo phosphorylated sites in the Spike protein of SARS-CoV2, could potentially uncover important novel regulatory mechanisms for SARS-CoV2.
Highlights
The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680SPRRAR↓SV687 forming a cleavage motif RxxR for furin-like enzymes at the boundary of S1/S2 subunits
We discovered that a motif RRxR, with a crucial P3 arginine, was required for cleavage of the S1/S2 site substrate constructs in vitro, while the motif in common with MERS-CoV (RxxR) was not sufficient for furin cleavage
We found that the R-x-x-R motif at S1/S2 in MERS-CoV has been considered as a furin cleavage site[13,14,30], it was cleaved by furin at very low efficiency (Fig. 1d,e)
Summary
The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680SPRRAR↓SV687 forming a cleavage motif RxxR for furin-like enzymes at the boundary of S1/S2 subunits. An analogous cleavage motif was present at S1/S2 of the Spike protein of the more distant Middle East Respiratory Syndrome coronavirus MERS-CoV. The coronavirus Spike glycoprotein mediates the entry of the coronavirus into the host cell[7] It is composed of two subunits (Fig. 1a): S1, which binds the angiotensin-converting enzyme 2 (ACE2) on the host cell s urface[8,9], and S2, which mediates membrane fusion[10,11]. After the release of the SARS-CoV2 sequence, it was promptly realized that an analogous R-x-x-R motif was present in the Middle East Respiratory Syndrome coronavirus MERS-CoV that caused an outbreak in 2 0124. It was reported that the cleavage of the Scientific Reports | (2020) 10:16944
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