title: Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A.
abstract: The large GTPase atlastin belongs to the dynamin superfamily that has been widely implicated in facilitating membrane tubulation, fission, and in select cases, fusion. Mutations spread across atlastin isoform 1 (atlastin-1) have been identified in patients suffering from hereditary spastic paraplegia (HSP), a neurodegenerative disorder affecting motor neuron function in the lower extremities. On a molecular level, atlastin-1 associates with high membrane curvature and fusion events at the endoplasmic reticulum and cis-Golgi. Here we report crystal structures of atlastin-1 comprising the G and middle domains in two different conformations. Although the orientation of the middle domain relative to the G domain is different in the two structures, both reveal dimeric assemblies with a common, GDP-bound G domain dimer. In contrast, dimer formation in solution is observed only in the presence of GTP and transition state analogs, similar to other G proteins that are activated by nucleotide-dependent dimerization. Analyses of solution scattering data suggest that upon nucleotide binding, the protein adopts a somewhat extended, dimeric conformation that is reminiscent of one of the two crystal structures. These structural studies suggest a model for nucleotide-dependent regulation of atlastin with implications for membrane fusion. This mechanism is affected in several mutants associated with HSP, providing insights into disease pathogenesis.
authors.affiliation: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Byrnes
authors.forename: Holger
authors.initials: H
authors.lastname: Sondermann
mesh_terms: D018360:Crystallography, X-Ray; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006153:Guanosine Diphosphate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008561:Membrane Fusion / Q000235:genetics; D008565:Membrane Proteins; D008958:Models, Molecular; D009154:Mutation; D020336:Paraparesis, Spastic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D008565:Membrane Proteins; D006153:Guanosine Diphosphate; C440006:ATL1 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins