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 (cPLA(2)) binds via its calciumdependent C2 domain (cPLA(2)-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 cPLA(2) 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 cPLA(2) at cytoplasmic resting-Ca2+ concentrations. cPLA(2)-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 cPLA(2)-C2 to detect stretched membranes with antibody-like affinity, providing a quantitative basis for understanding mechanotransduction by C2-like domains.

Automated summary

This study investigates the mechanosensitive adsorption of cPLA(2) and its C2 domain to nuclear membranes and artificial lipid bilayers. It is found that stretching the membranes increases the sensitivity of all tested domains to Ca2+ and the binding affinity of cPLA(2)-C2 to stretched membranes is 50 times higher than that to unstretched membranes. These findings provide a quantitative basis for understanding mechanotransduction by C2-like domains.