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COVID-19 is caused by the new coronavirus SARS-CoV-2. This virus has a characteristic virus hull featuring surface proteins which are commonly called “spikes”. Protruding from the viral hull like “spikes of a crown”, they give the coronavirus its name (corona = crown). These proteins make the first contact with human cells and are akin to keys that use a human receptor called “angiotensin-converting enzyme2” (ACE2) as a backdoor to gain access to and infect the cell.
1. Fuction of ACE2
ACE2 is a membrane protein which is anchored in the human cell membrane of epithelial cells. This type of cells can be found on the surface of lung, intestine, heart and kidney tissue. As a type I membrane protein, its primary function is to take part in maturation of angiotensin, a peptide hormone which controls vasoconstriction and blood pressure. ACE2 can be compared to a lock which can be unlocked by the coronavirus spike protein. The virus can then enter the cell and hijack its functions to reproduce itself, thus causing the Covid-19 infection which poses a serious danger to humanity, especially for older people and people with pre-existing conditions. For this reason, one approach to combating SARS-CoV-2 is to target and inhibit the spike to prevent infection. In order to do so, knowledge of the structural features of the spike and its interaction processes with ACE2 are indispensable. (Further information about how macromolecular structures are visualized can be found on our homepage: https://insidecorona.net/visualizing-macromolecular-structures/)
2. Spike: Structure and Fusion Mechanism
The Spike protein has a trimeric shape comprising three identical monomeric structural elements. Each of these monomers can fold out akin to a modern car key with a fold-out key element with specific teeth on its surface. This fold-out key element is the so-called “receptor binding domain” (RBD). The spike can only interact with ACE2 when its RBD is in a folded-out position, exposing its teeth, or “receptor binding motive” (RBM). As the name suggests, it comprises a motive of different amino acids which then can bind and unlock the ACE2 receptor. This key lock mechanism triggers a cascade of events initiating fusion with the host cell. First, protein scissors are recruited to the binding site. These scissors (furin & transmembrane serine protease 2) cleave the spike protein for subsequent activation. The active spike molecule then rearranges itself to form a long structural “hook” (formed of HR1/ HR2 and FP see Fig.2) that brings the epithelial cell and viral cell membrane into close proximity for fusion. Once the fusion is completed, the path for the virus is clear to transfer its genome encoded in ribonucleic acid (RNA) into the host cell. This successful transfer then enables the virus to multiply itself and finally spread from cell to cell, causeing Covid-19 in its wake.
3. Evading the Immune System with Carbohydrate Chains
The human immune system normally recognizes the surface proteins of foreign organisms such as viruses or bacteria and reacts with an immune response to combat them. Spike proteins are such surface proteins but because of structural peculiarities, the coronavirus evades both the innate and the adaptive human immune system. The secret of these structural peculiarities are the N-glycans. These are long carbohydrate chains which sit on spike’s surface. Each spike comprises 66 N-glycans forming a protective shield around the protein. Hence the human immune system has problems recognizing spikes and identifying the coronavirus as an enemy.
The COVID 19 pandemic has a massive impact on our lives, our health and the global economy. Scientists around the world are trying to develop new drugs to combat the virus. Since the spike plays a critical role in the infection process, it is a prime target for drug development against the pandemic. One drug approach to inhibit the interaction between spike and the ACE2 receptor is to cap the spike protein using antibodies. Antibodies are proteins, normally produced by the human immune system to fight viruses. The idea is to treat patients with antibodies that cap the RBD of spike, thus preventing interactions with ACE2. This would lead to a nonfunctional spike, blocking the coronavirus from entering the cell (The key would no longer fit the lock). Another approach includes the development of small molecules that target and inactivate the protein scissor transmembrane serine protease 2 (see chapter 2), as the spike’s functionality depends on its cleavage activity. Since the spike protein decorates the virus hull, it could even be part of a potential vaccine. For this reason, the spike protein could also become the key in the molecular fight against COVID-19.