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A study by the University of Valencia (UV) and the Spanish National Research Council (CSIC) has revealed that a previously little-studied region of the SARS-CoV-2 coronavirus Spike protein is essential for the virus to enter human cells. The work, published in Communications Biology, shows that the so-called transmembrane domain is not merely an “anchor” securing the protein to the viral membrane, as previously thought. Instead, this component is active and fundamental to the infection process.
The Spike protein is the key that the coronavirus uses to recognise and fuse with human cells. “Understanding every cog in the coronavirus machinery is crucial if we want to be prepared for future variants or even for other similar viruses”, emphasises Luis Martínez Gil, principal investigator and coordinator of the study, as well as lecturer in the Department of Biochemistry and Molecular Biology at the University of Valencia.
The research was carried out by the Membrane Proteins Laboratory (led by Ismael Mingarro) of the Faculty of Biological Sciences — University Institute of Biotechnology and Biomedicine (Biotecmed) of the University of Valencia, in collaboration with researchers from the Institute for Integrative Systems Biology (I2SysBio, a joint UV–CSIC centre).
Since the start of the pandemic, the external parts of the coronavirus have been examined in detail, but the role of its terminal segment — the part that 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 infective capacity”, explains Juan Ortiz Mateu (Biotecmed), first author of the study.
The research also shows that this region exhibits very few alterations across different coronavirus variants. This strengthens the idea that the transmembrane domain of the Spike protein is not simply a region that inserts the protein into the membrane, but a key element that modulates interactions on which infective efficiency depends.
During the study, the researchers introduced mutations at specific sites in the proteins and observed a reduction in the virus’s ability to enter cells. They also found that the transmembrane domain helps the Spike protein assemble into groups of three — the structure required for effective fusion of the virus with the cell.
The authors argue that, in addition to improving our understanding of how the virus functions and develops, this research allows the focus to be placed on discovering new drugs and treatments targeting this part of the protein. In other words, it opens the door to exploring therapeutic approaches that had not previously been considered, as the transmembrane domain could be used to intervene and block the Spike protein, thereby hindering infection.
The study was funded by several public programmes within the projects of the Spanish Ministry of Science, Innovation and Universities, the Spanish Research Agency, and the European Union, as well as by the Prometeo research programme of the Valencian Regional Government.
Article reference: Ortiz-Mateu, J., et al. The sequence and structural integrity of the SARS-CoV-2 Spike protein transmembrane domain is crucial for viral entry. Commun Biol 8, 1579 (2025). https://doi.org/10.1038/s42003-025-08974-0
