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

Significance A cell must be able to measure whether the lipid membranes that surround its insides are stretched. Currently, mechanosensitive ion channels are the best-studied class of membrane tension sensors, but recent work suggests that peripheral membrane enzymes that gauge nuclear confinement or swelling during cell migration or upon tissue injury constitute a second class. The mechanosensitivity of these enzymes derives from their calcium-dependent (“C2-like”) membrane-interaction domains. Although these can be found in many important signaling proteins, they have remained virtually unstudied as mechanotransducers. How membrane tension controls these domains and what features render them mechanosensitive is unclear. Here, we show that membrane tension-sensing by C2-like domains is mediated by a synergy between mechanosensitive calcium-binding and membrane insertion.