MIMIC · Mapping and modulating integrin mediated interactions

Mapping and modulating integrin mediated interactions

All complex organisms are composed of millions of living cells that are in constant interaction with each other and with the environment. These interactions are brought about by proteins embedded in the cell membranes, called receptors, forming interactions with proteins and other molecules outside of the cell, called ligands. These extracellular proteins can be signals that change the cells’ behaviour (for example hormones), can be on the surface of other cells (forming cell-cell contacts, for example in tissue formation or during the activity of immune cells), or even pathogens such as viruses (to get inside the cell where they replicate). 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.

Data: CORDIS, © European Union