FIGURE 7:

Model for plasma membrane targeting of mDia2. Step 1: Phospholipid binding. The initial targeting event occurs while mDia2 is still autoinhibited, yet its BD is accessible to bind acidic phospholipids of the plasma membrane through electrostatic interactions. This transient binding allows mDia2 to linger at the plasma membrane until it encounters active GTPase Rif there. Step 2: Weak Rif binding. Active Rif binds to G region of mDia2. Now, the mDia2 dimer is additionally attached to the plasma membrane via weak interaction with the membrane-associated active Rif. The BD-G–bound Rif begins to displace the DAD peptide of the C terminus from DID (black arrows). Step3: Strong Rif binding and activation. Rif, possibly in concert with additional coactivator(s), causes disruption of the DID/DAD bond. This event allows DID to bind Rif, resulting in a more stable association of mDia2 with the membrane and also relieves autoinhibition of mDia2 to allow the FH1-FH2 domains to nucleate and elongate actin filaments.