Question

S proteins for Covid19

The S protein has two major domains. S1 and S2. On the molecular level, what are considered the two major roles of this S protein?

S1

S2

Answer 1

4. [4] SARS-CoV-2 virus or COVID 19 virus belongs to the coronavirus family of viruses. These are enveloped positive sense RNA viruses with spikes present on virus envelope. Primary route of entry for the virus is via droplet secretion from infected individuals. The virus infects the nasopharyngeal cells by attaching to the ACE2 (angiotensin converting enzyme 2) receptors on host cells. The S glycoprotein that makes up the spikes on the envelope is major protein involved in attachment to the ACE2 receptor. The Ectodomain of S protein has two domains- N terminal S1 and C terminal S2 domains which are involved in attachment and membrane fusion. Transmembrane domain, an amphipathic alpha helix, attaches the S protein S2 domain to the envelope. S protein has 2 major roles- attachment to host cells and fusion of the viral enveloped capsid with host cell membrane.

S1

S2

S1 domain is involved in attachment to host cell by directly binding to ACE2 receptor on cells. S1 domain has two subdomains: N terminal and C terminal domain. Both these domains have the receptor (ACE2) binding site. The S1 domain varies among many coronavirus and is therefore major site for mutations. In order that S1 domain binds to the ACE2 receptor, there is activation of S protein by a protease known as TMPRSS2. The receptor binding domains are responsible for immune surveillance evasion and hence, longer incubation period of the virus.

S2 domain is involved in membrane fusion. It is most conserved domain. This domain has putative fusion peptide a transmembrane domain, and cytoplasmic domains. Tetrad repeats HR1 and HR2 are present which have hydrophobic repeats required for membrane fusion. For membrane fusion to occur and formation of endosomal vesicles, the lysosomal proteases will cleave the spike protein at S1/S2 boundary. S1 dissociates and the S2 domain undergoes conformational changes. The fusion peptides are unmasked by actions of cathepsin L1 protease. This process is highly regulated as it is an irreversible process. This results in membrane fusion of the capsid with the endosomes. Fusion with endosomal membrane is via a clathrin mediated endocytosis process.