Journal Article

The sequence at Spike S1/S2 site enables cleavage by furin and phospho-regulation in SARS-CoV2 but not in SARS-CoV1 or MERS-CoV

Faustova, Ilona, Örd, Mihkel, Loog, Mart

2020

Overview

The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680 S PRRA R↓SV 687 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 R R xR 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 S PRRAR↓ S V 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.

• Publisher: Nature Publishing Group UK
• Subject: 631/337 / 631/45 / Amino Acid Motifs - genetics / Amino Acid Sequence / Betacoronavirus - genetics / Furin - metabolism / Humanities and Social Sciences / Middle East Respiratory Syndrome Coronavirus - genetics / multidisciplinary / Phosphorylation / Proteolysis / SARS Virus - genetics / SARS-CoV-2 / Science / Science (multidisciplinary) / Spike Glycoprotein, Coronavirus - genetics / Spike Glycoprotein, Coronavirus - metabolism / Virus Internalization