Mechano-redox control of integrin de-adhesion

Many proteins embedded in a cell’s surface allow the cell to interact with its surroundings. Integrins are a group of cell surface proteins that have many uses in different cells. Integrins become activated when they come into contact with other specific proteins, which like other molecules that bind to proteins are referred to collectively as “ligands”. Much research has focused on how ligands become attached to integrins and how this activates these cell surface proteins. Yet how integrins release ligands and become inactive has not been studied before. One type of integrin, called αIIbβ3, is involved in blood clotting. Found on the surface of blood platelets – the fragments of cells in the blood that play a central role in clotting, this integrin binds to a ligand called fibrinogen. Fibrinogen links platelets together to form clots by building bridges between integrins. Passam, Chiu et al. have now studied platelets from donated human blood to understand how the integrin αIIbβ3 disengages from fibrinogen. The investigation showed that an enzyme called ERp5 aids the release of fibrinogen from the integrin. ERp5 can be released by blood vessel walls and by activated platelets. The experiments revealed that ERp5 breaks a chemical link, called a disulfide bond, in the integrin, but only when the protein is already bound to its ligand. Breaking the disulfide bond (a chemical process known as reduction) changes the integrin’s structure so that it lets go of fibrinogen. Moreover, when physical forces such as blood flow put the integrin under strain, the ERp5 enzyme becomes more effective. These findings show how ligand binding and mechanical force work together to control the breaking of a chemical bond in a human integrin. This chemical event then in turn controls the release of the integrin's ligand. It is possible that other protein-protein interactions may involve similar mechanisms, but this remains to be explored. Lastly, Passam, Chiu et al. suggest that the release of fibrinogen might help to limit the growth of blood clots so they do not block the blood vessels. Further studies should test this hypothesis. Inappropriate clotting can have severe health effects including heart attacks and strokes. As such, this investigation may hint at a more subtle way to regulate clotting through integrin αIIbβ3, such as boosting fibrinogen release to see if it helps slow or reduce clotting without stopping it altogether.