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Model illustrating the activation of Tcb3 at ER–PM membrane contact sites. When cytosolic Ca2+ concentration is low, Tcb3 loosely binds to the PM. The SMP domain dynamically interacts with the membranes, slowly transferring lipids. Once the cytosolic Ca2+ concentration increases, the C2C and C2D domains bind to the PM tightly, strengthening the ER and the PM connections and enhancing the ER–PM lipid exchange. ER, endoplasmic reticulum; PM, plasma membrane.
