Intermolecular association of the variable domain of dynamin related protein 1 in crowding conditions suggests a role in dynamin assembly

Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a “variable domain” (VD) important for regulation. For the mitochondrial fission dynamin, Drp1, a regulatory role for the VD is demonstrated by mutations that can elongate, or fragment, mitochondria. How the VD encodes inhibitory, and stimulatory, activity is an unresolved issue. This talk focuses on the behaviour of isolated VD from Drp1 isoform 1. Using spectroscopy methods (NMR and circular dichroism) and molecular dynamics (MD) simulations, this VD is shown to be intrinsically disordered (ID). Somewhat surprisingly, microscopy and light scattering studies also indicate that this VD in solution undergoes a liquid-liquid phase separation under the influence of an osmolyte that normally induces ID proteins to fold. Interestingly, these crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid. MD simulations suggest this liquid-liquid phase separation arises from weak, multivalent interactions similar to other systems involving intrinsically disordered regions. These new findings support a model where the variable domain mediates phase separation that enables rapid tuning of Drp1 assembly necessary for fission.