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SARS-CoV-2 Spike Protein

The SARS-CoV-2 spike protein (Severe acute respiratory syndrome coronavirus 2) is a protein that has emerged from the COVID-19 virus beginning in December 2019. Both the S1 and S2 subunits are the last two regions that manage the processes of the receptor binding and the membrane fusing. In the S1 subunit, it is composed of an N-terminal, receptor-binding domain, and the fusion of peptides, heptapeptide 1 and 2, TM domain, and cytoplasmic domain fusion are the reason for viral fusion and entry. In the S2 subunit, the S-protein trimers have a shape of a crown-like looking halo that is on the surrounding area of the viral particle. Because of the structure of the coronavirus S protein monomers this causes both the S1 and S2 subunits to be formulated into a “bulbous head and stalk region”. In the native state– the protein is folded to be able to operate and function properly. In this case the SARS-CoV-2 spike protein begins to exist as an inactive precursor when in this specific state. However, in a viral infection state SARS-CoV-2 spike protein the target cell's proteases will activate the S-protein which is being cleaved into both the S1 and S2 subunits. As a result, this allows for the activation of the membrane fusion after the result of viral entry are in the targeted cells.^[1]

Function

The SARS-CoV-2 spike protein helps extract antibodies that neutralize viruses into the body. To enter a cell and start an infection, the spike protein in SARS-CoV-2 (SARS-2-S) interacts with the human ACE2 receptor. The ACE2 (Angiotensin-converting enzyme 2) is an enzyme that can be found in the membrane of cells in the following: intestines, kidney, testis, gallbladder, and heart. The SARS-2-S is split into S1 and S2 subunits, with S1 functioning as the receptor-binding component and S2 as the membrane-fusion subunit.^[2] The S protein has the following: extracellular N-terminus, a transmembrane domain that is being anchored into the viral membrane, and a short intracellular C-terminal. The S typically exists in a metastable– where it will have no small disturbances, prefusion conformation.^[3] Initially, when the virus begins to interact with the host cell, this causes structural rearrangement of the S protein.^[4] The rearrangement of the S protein then allows the virus to be able to fuse with the host cell membrane. The spikes of the protein are coated with polysaccharide molecules to be able to act like a form of camouflage. This allows for the host immune system to not bind to the spikes during entry.

Disease

The SARS-CoV-2 virus causes an infectious disease called Coronavirus (COVID-19). The COVID-19 illness has had a significant global impact on human health.^[5] Coronavirus emerged in December of 2019 and is still present as of 2022. Most people infected with the disease experience an array of symptoms including fever, headaches, fatigue, sore throat, cough, etc. The spike protein is on the surface of the SARS-CoV-2 virus which then initiate infection in host cells.^[3]

Mutations

The viral DNA experiences numerous spike protein changes to enable it to infect a new mammalian host and leap species. The D614G mutation is a common mutation in SARS-CoV-2 spike protein. It has no effect on the affinity of monomeric spike protein for ACE2 and residue 614 is found outside the receptor binding domain (RBD). The mutation dramatically increases the virus's capacity to infect and spread. ^[6] Drugs created to target protein-protein interactions, such as vaccines, may be affected by mutations found at the interface between the ACE2 receptor and the spike protein. ^[7]

Structural Highlights

The SARS-CoV-2 spike protein has a primary, secondary, tertiary, and quaternary structure. The motif present in the SARS-CoV-2 spike protein is the beta sandwich– where there are 1273 amino acids that occur in the protein. Beta sandwiches are characterized by having two opposed antiparallel beta-sheets. The domains are the following: N-terminus signal peptide, a receptor-binding fragment S1 and fusion fragment S2. The S1 is divided into N-terminal domain (NTD), receptor-binding domain (RBD) and C- terminal domains (CTD1 and CTD2). The quaternary structures are both dimers and trimers; the quaternary symmetry is asymmetric C1.^[8] The 3-D form of the protein plays a role in receptor recognition cell membrane fusion process that has two subunits: S1 and S2. The Angiotensin-converting enzyme 2 is recognized and bound by the receptor-binding domain of the S1 subunit. Through the two-heptad repeat domain, the S2 subunit facilitates viral cell membrane fusion, resulting in a six helical bundle. ^[1]