Session Speaker

Ring Stabilizers: Compounds that Increase Dynamin GTPase Activity by Promoting Ring Assembly
Nick N Gorgani, Chandra S Malladi, Anna Mariana, Annie Quan, Gordana Hadzic, Sanja Sever, Adam McCluskey and Phillip J Robinson
Australia

Dynamin is an intracellular enzyme with multiple domains that plays crucial roles in many biological processes such as endocytosis, antigen presentation, actin assembly, cell cycle and synaptic transmission. Under well-defined conditions, tetrameric dynamin can self assemble into two distinct structural states that show elevated GTPase activity: (i) dynamin in solution at relatively high concentrations (300-1000 nM) can oligomerize to form ring structures comprising about 26 dynamin molecules, whereas (ii) upon recruitment to the plasma membrane, or in the presence of liposomes, dynamin at low concentrations (10-20 nM) can tubulate the lipid membranes to form a helical structure that results in membrane fission. Self-assembly of dynamin to single rings or to helices results in 10 and 800 fold increased GTPase activity, respectively.

To modulate the biological function(s) of dynamin, we have generated several classes of dynamin inhibitors. We now report that a subclass of these inhibitors termed “ring stabilizers”, are a distinct subset of dynamin inhibitors with dual actions. In the presence of liposomes ring stabilizers inhibit the lipid-stimulated dynamin GTPase activity, whereas in the absence of liposomes they promote self assembly of single rings at low dynamin concentrations (50-200 nM), thereby stimulating the basal activity of dynamin. Structure activity relationship studies revealed specific ring stabilizers that only potentiate formation of rings with no significant inhibition of helix activity. Electron microscopy confirmed that ring stabilizers promote dynamin assembly into rings of relatively uniform diameter. Ring stabilizers may therefore provide novel tools for probing the cellular functions of the dynamins.