Synergistic effect of PIP₂ and PIP₃ on membrane-induced phase separation of integrin complexes

The assembly of integrin adhesion complexes at the inner leaflet of the plasma membrane regulates cell adhesion to the extracellular matrix. The multivalent protein interactions within the complexes and with the cell membrane display characteristics of membrane-associated biomolecular condensates driven by liquid-liquid phase separation. The composition of lipids and the distribution of the cell membrane are crucial for forming integrin adhesion complexes. Here, we report that phosphatidylinositol 4,5-bisphosphate (PIP₂) and phosphatidylinositol (3,4,5)-trisphosphate (PIP₃) in the model membrane synergistically regulate the formation of membrane-induced integrin adhesion condensates, which consist of β1 tails, kindlin, talin, paxillin, and focal adhesion kinase. We show that the preferential bindings of kindlin to PIP₃ and talin to PIP₂ enhance their recruitment to the membrane, which in turn increases the probability of membrane-associated phase separation. Our results indicate that modulating the intricate balance of membrane composition is a strategy to localize integrin adhesion complexes and optimize their density on lipid membranes.