A synergy between mechanosensitive calcium- and membrane-binding mediates tension-sensing by C2-like domains

When nuclear membranes are stretched, the peripheral membrane enzyme cytosolic phospholipase A2 (cPLA₂) binds via its calcium-dependent C2 domain (cPLA₂-C2) and initiates bioactive lipid signaling and tissue inflammation. More than 150 C2-like domains are encoded in vertebrate genomes. How many of them are mechanosensors and quantitative relationships between tension and membrane recruitment remain unexplored, leaving a knowledge gap in the mechanotransduction field. In this study, we imaged the mechanosensitive adsorption of cPLA₂ and its C2 domain to nuclear membranes and artificial lipid bilayers, comparing it to related C2-like motifs. Stretch increased the Ca²⁺ sensitivity of all tested domains, promoting half-maximal binding of cPLA₂ at cytoplasmic resting-Ca²⁺ concentrations. cPLA₂-C2 bound up to 50 times tighter to stretched than to unstretched membranes. Our data suggest that a synergy of mechanosensitive Ca²⁺ interactions and deep, hydrophobic membrane insertion enables cPLA₂-C2 to detect stretched membranes with antibody-like affinity, providing a quantitative basis for understanding mechanotransduction by C2-like domains.