Coronavirus
Structural Task Force

Spike Glycoprotein: Corona’s Key for Invasion

Für diesen Beitrag exisitiert leider keine deutsche Übersetzung.

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.

SARS-COV2 Animated picture. Realistic surface and spike proteins with glycosylation. Image: Thomas Splettstoesser; www.scistyle.com
Fig. 1. SARS-COV2 Animated picture. Numerous spike proteins, coloured in green, protrude from the virus hull which is coloured in brown. Spikes enable the coronavirus to invade human epithelial cells. Image: Thomas Splettstoesser; www.scistyle.com

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

Fig. 2. Image of a spike protein (green) protruding out of the viral envelope (brown). This image shows the structure of a spike protein divided into several subdomains. Each subdomain comprises a specific function necessary for binding and fusion. The transmembrane domain anchors the spike protein in the virus membrane.  Heptat repeat 1, 2 and the fusion peptide play key roles in mediation of the fusion process and with the RBD domain, the virus makes contact to human cells. Note that only “stumps” of carbohydrate chains are shown. Image: Thomas Splettstoesser; www.scistyle.com

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.

Fig. 3. This image shows a spike protein in complex with the human ACE2 receptor. (PDB:6vsb/6lzg). Left: The structure of a spike protein coloured in orange in complex with the human ACE2 receptor coloured in light orange. The white box shows the interaction site which is shown enlarged in the image ion the right. Right: The interaction site between spike and ACE2. Spike's "receptor binding domain (RBD)" includes a "receptor binding motif (RBM)" whose amino acids interact with those of the human receptor through hydrophilic interactions. These amino acids are shown as sticks protruding from the RBM and ACE2. Image: Sabrina Stäb

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.

Fig. 5. Ribbon diagrams of a spike trimer with N-glycans on its surface coloured in cyan (PDB: 6vxx). In Image a, the spike protein is shown sideways and in b, the trimer can be seen from above. Unfortunately, both X-ray crystallography and cryo-EM cannot resolve long carbohydrate chains, so the structures of the chains shown in Figure 4 contain a maximum of three sugar monomers, while in most cases, the carbohydrate chains are much longer, covering most of the contact surfaces of the upper spike protein. Image: Sabrina Stäb

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.

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