We usually think of proteins as being folded polypeptide chain structures. However ~30% of the human protein sequence space is considered to be natively disordered (or unstructured). It turns out that short stretches of amino acids within these flexible unstructured regions may have functions such as binding to another protein and/or being sites of post-translational modification such as phosphorylation. We term these sites Short Linear Motifs (SLiMs) as the sequence is important for function. Regulatory and signalling networks of our cells utilise SLiMs as key elements in their information processing systems. When a pathogen invades a cell it will attempt to hijack the networks in order to repurpose the host to optimise its own reproduction. This implies that there is a potential therapeutic strategy to revert the hijacking process: Can we “drug the cell to cure the pathogen”? The SARS2 Spike protein binds to the ACE2 receptor on the surface of cells lining the respiratory tract and then gains entry via a mechanism termed receptor mediated endocytosis. Essentially, the bound receptor triggers formation of vesicles that are then processed internally until the viral RNA is released and begins the replicative process. ACE2 has a small tail sequence projecting into the cell. When we examined the tail with our collection of SLiMs in the ELM server (http://elm.eu.org), we found a number of signatures for SLiMs involved in endocytosis and vesicle processing (see arXiv preprint). These signatures are conserved in other vertebrate ACE2 sequences, suggesting that they are functional. Experimental validation is required because it is difficult to get good statistical support given the minimal amount of sequence information in these short motifs. Once that is forthcoming, then drugs which slow down viral import could be tested in cell culture systems.
Mészáros et al. Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications. https://arxiv.org/abs/2004.10274
Davey, N.E., Travé, G., Gibson, T.J., 2011. How viruses hijack cell regulation. Trends Biochem. Sci. 36, 159–169.
Kumar, M., Gouw, M., Michael, S., Sámano-Sánchez, H., Pancsa, R., Glavina, J., Diakogianni, A., Valverde, J.A., Bukirova, D., Čalyševa, J., Palopoli, N., Davey, N.E., Chemes, L.B., Gibson, T.J., 2020. ELM-the eukaryotic linear motif resource in 2020. Nucleic Acids Res. 48, D296–D306.