Periodic Reporting for period 1 - MIMIC (Mapping and modulating integrin mediated interactions)
Reporting period: 2020-01-07 to 2022-01-06
One of the most important receptors on the surface of human cells are the integrins. This receptor family has 24 members and while all of them are similar in their characteristics, they all recognise slightly different ligands. Virtually all of our cells have various integrins on their surface that aid the cell in performing its function. For example, our platelets have a very high number of the integrin called alpha(IIb)beta(3), and these integrins can bind to large proteins in the blood in order to clump together and clog wounds to stop bleeding. However, when the regulation of the platelets goes wrong, this clumping together can lead to very serious conditions, such as thrombosis. In addition to thrombosis, the activity and misregulation of integrins have been connected to a very wide range of other diseases as well, such as Crohn’s disease, multiple sclerosis, or cancer.
In light of their importance, it is clear why integrins have been the focus of biological research for many years. Until now about 80,000 scientific papers have been published about how integrins fulfill their functions and how they are misregulated in diseases. However, there are currently only 6 drugs used in clinics that target integrins, albeit many more were in development over the years. The fundamental problem that hinders efficient drug development is that integrins are very large and complex receptors and we do not fully understand how they recognise their ligands and what these interactions do precisely.
The main objective of MIMIC is to understand which integrin recognises which ligands by combining computational modeling and experimental biology. Based on the interactions between integrins and various ligands already described, we build models that can capture the most important features of these ligands that determine whether they can bind to integrins. Once these models are accurate enough, we can find new integrin ligands in various organisms, going beyond human proteins and potentially understanding how certain viruses - such as SARS-CoV-2 - cause diseases. This knowledge can help to better understand how our cells work and can also provide targets for future pharmaceutical drug development to combat severe and life-threatening diseases.
Having these models enabled the search for new integrin ligands that have never been measured yet. Amongst the newly identified integrin ligands, we found several that can be connected to various proteins of the SARS-CoV-2 virus. We noticed that based on its sequence and structure features, the Spike protein of the virus contains a likely binding site for integrins. Previously it was known that the human cell receptor for the virus is a protein called ACE2, but this finding indicated that in addition, SARS-CoV-2 uses integrins as well to infect human cells. Further analysing ACE2 and integrins, we found that these receptors are likely to be able to interact with other proteins inside the cell that are connected to various processes, most notably endocytosis and autophagy - the process of the cell engulfing material from the outside and digesting certain parts on the inside. These interactions were experimentally verified by our collaborators. Both processes are known to be linked to viruses in general and our findings offer ways to potentially counteract the viral infection with know drugs that were developed for other purposes (https://www.science.org/doi/10.1126/scisignal.abd0334).
In addition to Spike, we suspected that the viral protein called ORF7a is likely to bind to integrins, but upon experimental testing, this turned out to be false. However, by now we know that this protein also binds to some other receptor on the surface of immune cells and is likely to influence how the immune system works. We are currently devising experiments to determine which of the 5000 cell surface receptor ORF7a binds to, so we can later develop strategies to counteract this interaction thereby potentially boosting the immune response to viral infection.
MIMIC also served with many other new candidates for integrin binding. We do not have the capacity to test all of these within the framework of the project, and therefore we make all of this data public, including the results of the literature searches, the built models, and the found candidate ligands for other members of the community to use. These results were being communicated in peer-reviewed scientific articles, as well as conference talks, Twitter posts (@_BalintMeszaros), press releases (https://www.embl.org/news/science/protein-sequences-and-sars-cov-2/) and YouTube videos (https://www.youtube.com/watch?v=Hyt-IbJ2WJc).