The spike protein is a glycoprotein that studs the surface of many enveloped viruses, including coronaviruses like SARS-CoV-2. It mediates the virus’s entry into host cells. This protein is prominent on the viral surface, giving coronaviruses their characteristic “corona” or crown-like appearance. Because the spike protein first interacts with the host, it is the primary target for the body’s immune response and most vaccine development efforts.
Anatomy of the Spike Protein
The spike protein is a large, complex structure that exists as a homotrimer, formed by three identical protein units clustered together. This trimeric arrangement gives the protein a shape often likened to a stalk with a globular head, projecting approximately 20 nanometers from the viral membrane. The structure is also heavily decorated with sugar molecules, or glycans, which help shield the protein from the host immune system.
The protein is divided into two main functional segments: the S1 subunit and the S2 subunit. The S1 subunit forms the head and is responsible for binding to the host cell receptor. The S2 subunit forms the stalk that anchors the protein into the viral envelope and contains the machinery needed for membrane fusion. These two subunits remain noncovalently linked until the virus successfully attaches to a host cell.
Mechanism of Viral Entry
The process of viral entry begins with a precise “lock and key” interaction between the virus and the host cell. The “key” is the Receptor Binding Domain (RBD) on the S1 subunit, which must bind to the “lock,” the Angiotensin-Converting Enzyme 2 (ACE2) receptor found on human cells.
Once the spike protein successfully binds to the ACE2 receptor, it undergoes a significant conformational change. This change allows host proteases, such as TMPRSS2 (transmembrane protease, serine 2), to cleave the spike protein at specific sites, separating the S1 and S2 subunits. This cleavage, known as S protein priming, is necessary to activate the fusion mechanism.
The activated S2 subunit then drives the fusion of the viral membrane with the host cell membrane. As the S2 subunit refolds, it pulls the two membranes together, creating a channel. This channel allows the virus’s genetic material to be injected into the host cell’s cytoplasm, initiating the replication cycle.
Using the Spike Protein in Vaccines
The spike protein is the focus for vaccine developers because neutralizing it is the most direct way to stop viral entry. Vaccines introduce a harmless version of the spike protein to the immune system, teaching it to recognize and neutralize the protein. This approach is effective because antibodies capable of blocking the spike protein prevent its initial binding to the ACE2 receptor.
In many modern vaccines, such as those using mRNA or viral vector technology, the body’s own cells are temporarily turned into spike protein factories. The vaccine delivers genetic instructions that direct the host cell’s machinery to manufacture the spike protein. The cells then display these harmless spike proteins on their surface.
The immune system recognizes these produced spike proteins as foreign and generates a robust response, including neutralizing antibodies and T-cells. If the person is later exposed to the actual virus, the immune system quickly deploys these antibodies to bind to the spike proteins, blocking its ability to attach to host cells and preventing infection. To maximize the immune response, developers often modify the genetic instructions to stabilize the spike protein in its pre-fusion conformation.
Protein Mutations and Viral Variants
The spike protein’s constant interaction with the host environment makes it highly susceptible to genetic changes. As the virus replicates, errors in copying its genetic code lead to mutations in the gene that codes for the spike protein. These mutations are the driving force behind the emergence of new viral variants.
A significant consequence of these mutations is a change in the efficiency of the Receptor Binding Domain (RBD). Alterations in the RBD can strengthen the protein’s binding affinity to the ACE2 receptor, resulting in increased transmissibility. Other mutations can cause structural changes that allow the virus to evade recognition by antibodies, a phenomenon known as immune escape. This often necessitates the development of updated vaccines that target the spike protein sequences of newer variants.