THE DYNAMIN SUPERFAMILY: UNIVERSAL MEMBRANE TUBULATION AND FISSION MOLECULES?
Gerrit J. K. Praefcke and Harvey T. McMahon
Dynamins are large GTPases that belong to a protein superfamily that, in eukaryotic cells, includes classical dynamins, dynamin-like proteins, OPA1, Mx proteins, mitofusins and guanylate-binding proteins/atlastins. They are involved in many processes includingbudding of transport vesicles, division of organelles, cytokinesis and pathogen resistance. With sequenced genomes from Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, yeast species and Arabidopsis thaliana, we now have a complete picture of the members of the dynamin superfamily from different organisms. Here, we review the superfamily of dynamins and their related proteins, andpropose that a common mechanism leading to membrane tubulation and/or fission could encompass their many varied functions.
Membrane transport between compartments in eukaryotic cells requires proteins that allow the budding and SCISSION of nascent cargo vesicles from one compartment and their targeting and fusion with another. Just as SNARES are proposed to be essential for all vesicle-fusionreactions, so CLASSICAL DYNAMINS and DYNAMIN-RELATED PROTEINS have a similar appeal as the essential vesicle-scission molecules. They are involved in the scission of a wide range of vesicles and organelles, including CLATHRINCOATED VESICLES (CCVs), CAVEOLAE, phagosomes and mitochondria (FIG. 1, TABLE 1).Although DYNAMINS are not found in all budding reactions, the more places that are investigated, themore they will probably be found. The importance of dynamin was first discovered with the identification of temperature-sensitive mutants in Drosophila melanogaster 1,2 that gave rise to a paralytic phenotype. The locus was called shibire after the Japanese word for ‘paralysed’ (BOX 1). The shibire gene was then discovered to encode dynamin3,4. Dynamin had previously been characterized as a GTPasethat can associate with microtubules in vitro 5,6, and as a phosphoprotein in nerve terminals7. Since then, mutations that abolish the GTPase activity of dynamin have been widely used to characterize its functions. Dynamins are generally classified as ‘large GTPases’. This is to distinguish them from the small Ras-like and other regulatory GTPases, such as the well studied α-subunits ofheterotrimeric G-proteins and the translation factors of protein biosynthesis. In addition to having a larger GTPase domain, dynamin and dynamin-related proteins are distinguished from other GTPases by their oligomerization-dependent GTPase activation, their low GTP-binding affinities and the ability of many members of the dynamin family to interact with lipid membranes. There are many large GTPases in thedatabase — even in prokaryotes — that have homology to dynamin only in the GTPase domains, and do not have the additional domains that allow for self-oligomerization, so we do not count these as dynamin-related proteins.
Subdividing the dynamin superfamily
Cleavage of the vesicle from the parent membrane — as in the use of scissors to sever.
(solubleN-ethylmaleimidesensitive fusion protein attachment protein (SNAP) receptor). SNARE proteins are a family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity in vesicle trafficking. They can be divided into v-SNAREs and t-SNAREs on the basis of their localization.
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. e-mails:firstname.lastname@example.org; email@example.com
Overall architecture. The minimal distinguishing architectural features that are common to all dynamins and are distinct from other GTPases are the structure of the large GTPase domain (~300 amino acids) and the presence of two additional domains; the middle domain and the GTPase effector domain (GED),
NATURE REVIEWS | MOLECUL AR...