Dynamin: switch or pinchase?

What is it? Dynamin is a protein that is essential for severing nascent endocytic pits from the plasma membrane to form vesicles. According to whom you speak, dynamin is either a molecular ‘switch’, or a pinchase-like mechanoenzyme.What is a switch and what is a mechanoenzyme? Small GTPases of the Ras superfamily are often thought of as switches that control cellular events. These enzymes, when GTP-bound, are in an active state. Upon GTP hydrolysis, they become inactive and thus ‘off’. Hence, the protein switches between on and off states depending on if it is GTP- or GDP-bound. Kinesin, dynein, and myosin comprise three families of molecular motors or mechanoenzymes which bind and hydrolyze ATP, using the energy released to exert force and ‘do work’.What are some characteristics of switches and mechanoenzymes? Most switch-like GTPases have a very high affinity for GTP, a very slow rate of hydrolysis, and do not readily release GDP. In contrast, mechanoenzymes such as dynein, kinesin, and myosin have a low affinity for ATP, a high rate of hydrolysis, and readily release ADP.How is dynamin similar to a switch? Dynamin binds GTP, not ATP, and appears to have a GTPase effector domain or GED. Mutations in the GED, predicted to keep dynamin in the GTP-bound state, were found to stimulate rather than inhibit endocytosis. This suggested that dynamin was in an on state to facilitate the recruitment of other molecules that could perform the scission process. Thus, under normal conditions, endogenous dynamin would be predicted to hydrolyze GTP to switch off thereby releasing other scission factors into the cytosol.How is dynamin similar to a mechano-enzyme? Dynamin, like most motors, is a large protein, around 100kDa, has a low affinity for nucleotide, a high rate of hydrolysis, and readily releases the hydrolyzed nucleotide. In addition, like muscle myosins and flagellar dyneins, dynamin assembles into complex polymers.What is the controversy? Early data supporting the switch model have since been contradicted by convincing reports that mutations in the the dynamin GED do not inhibit GTPase activity as originally claimed. And mutations in the GTPase domain of dynamin that put the enzyme in a GTP-bound state inhibited rather than stimulated endocytosis. These studies are consistent with others suggesting that GTP-binding by dynamin is insufficient to support endocytosis; instead it must also hydrolyze GTP and undergo a conformational change to function.So which is dynamin? The current model is that dynamin is a large, GTP-binding mechanoenzyme that interacts with lipids, and undergoes conformational changes in response to nucleotide hydrolysis. The carboxyl terminus of dynamin contains a proline-rich domain (PRD) that extends outside the active complex to interact with multiple SH3-domain-containing proteins which implicates dynamin in signaling. It is an attractive proposal that dynamin polymers assemble at a variety of endocytic or secretory membrane compartments to constrict lipids while providing a structural scaffold for a variety of signaling proteins and lipids. There is certainly room for both models to coexist and it is well worth pursuing the scenario that dynamins participate in both cell signaling and vesicle formation through two activities: constriction and effector binding.Where can I find out more?