Myxovirus resistance (Mx) proteins restrict replication of numerous viruses. They are closely related to fission GTPases involved in membrane remodeling, such as dynamin.  Mx proteins may interact directly with viral structures, and can also form contractile rings that tubulate lipids. By analogy with dynamin, GTPase domain dimerization is thought to be involved in communication between spatially adjacent rings. However the mechano-chemical cycle of the Mx proteins has not been previously characterized. 

We have studied a human MxA variant in which the capacity for ring formation has been blocked, while the ability to hydrolyze GTP and dimerize reversibly has been retained. Crystallographic analysis shows that the GTPase domain of MxA dimerizes in a fashion analogous to dynamin. GTP binding is associated with a major repositioning of the lever arm which sits adjacent to the GTPase domain, while GTP hydrolysis returns the enzyme to its resting state. We propose a class of kinetic models for studying dissociable dimeric enzymes, and use them to explain the self-activated GTPase activity of MxA. Biophysical studies show that the GTPase domain dimer forms extremely transiently, and dimerization is not promoted by substrate binding. Therefore dimerization apparently functions to coordinate the activities of adjacent Mx rings, allowing the power strokes associated with GTP hydrolysis to be effectively synchronized.