The large
GTPase dynamin has an important membrane scission function in receptor-mediated endocytosis and other cellular processes. Self-assembly on
phosphoinositide-containing membranes stimulates
dynamin GTPase activity, which is crucial for its function. Although the
pleckstrin-homology (PH) domain is known to mediate
phosphoinositide binding by
dynamin, it remains unclear how this promotes activation. Here, we describe studies of
dynamin PH domain mutations found in
centronuclear myopathy (CNM) that increase
dynamin's
GTPase activity without altering
phosphoinositide binding. CNM mutations in the PH domain C-terminal α-helix appear to cause conformational changes in
dynamin that alter control of the
GTP hydrolysis cycle. These mutations either 'sensitize'
dynamin to
lipid stimulation or elevate basal
GTPase rates by promoting self-assembly and thus rendering
dynamin no longer
lipid responsive. We also describe a low-resolution structure of dimeric
dynamin from small-angle X-ray scattering that reveals conformational changes induced by CNM mutations, and defines requirements for domain rearrangement upon
dynamin self-assembly at membrane surfaces. Our data suggest that changes in the PH domain may couple
lipid binding to
dynamin GTPase activation at sites of vesicle invagination.