I2SysBio participates in the discovery of the role of the coronavirus "anchor": the less known part of the Spike protein is key to infection

A team from the Higher Council for Scientific Research (CSIC) and the University of Valencia (UV) has discovered that a hitherto little studied region of the coronavirus Spike protein SARS-CoV-2 is vital for the virus to enter human cells. The work, which appears published in the journal Communications Biology, demonstrates that the so-called transmembrane domain is not a simple anchor that attaches the protein to the virus membrane, as was previously thought. This part is active and basic in the infection process.

The Spike protein is the key that the coronavirus uses to recognize and fuse with human cells. "Understanding all the gears of the coronavirus machinery is essential if we want to be prepared for future variants or even other similar viruses," points out Luis Martínez Gil, principal investigator and study coordinator, Professor in the Department of UV Biochemistry and Molecular Biology.

The work has been carried out by the Membrane Protein Laboratory (directed by Ismael Mingarro) of the Faculty of Biological Sciences of the University Institute of Biotechnology and Biomedicine (Biotecmed) of UV, in collaboration with researchers from the Institute for Integrative Systems Biology (I2SysBio), located in the scientific-academic area of the University of Valencia Science Park (PCUV). 

Since the start of the covid-19 pandemic in 2020, the external parts of the coronavirus had been analyzed in detail, but the role of its final stretch, which crosses the viral membrane, had not been clarified. "Our results show that the sequence and structure of this region are critical: small changes are enough for the virus to lose much of its ability to infect", explains Juan Ortiz Mateu (Biotecmed), first author of the work.

Since the start of the covid-19 pandemic in 2020, the external parts of the coronavirus had been analyzed in detail, but the role of its final stretch, which crosses the viral membrane, had not been clarified. The results show that the sequence and structure of this region are critical: small changes are enough for the virus to lose much of its ability to infect

In addition, the research has concluded that this region presents few alterations in the different variants of coronavirus. Therefore, it reinforces the idea that this transmembrane domain of the Spike protein is not a region that only inserts the protein into the membrane, but is an important element that modulates interactions on which infectious efficiency depends.

During scientific exploration, the research staff introduced mutations in the specific sites of the proteins, and observed the reduced effectiveness with which the virus was able to enter the cells. It has also been revealed that the transmembrane domain helps the Spike protein unite in groups of three, the structure necessary for proper fusion of the virus to the cell.

The authors argue that this research, in addition to better understanding how the virus acts and develops, allows us to focus on the discovery of new drugs and treatments related to this part of the protein. That is, it opens the door to experiment with new therapeutic approaches that had not been previously studied, since one could use the transmembrane domain to intervene and block the Spike protein, and succeed in stopping the infection.

The work has been funded by several public programmes, within projects of the Ministry of Science, Innovation and Universities, the State Research Agency and the European Union. Also from the Prometeo research project of the Generalitat Valenciana.