Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 6; pp. 2216 - 2221
• Main Authors: Byrnes, Laura J, Sondermann, Holger
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.02.2011; National Acad Sciences
• Series: From the Cover
• Subjects: Biological Sciences; Crystal structure; Crystallography, X-Ray; Crystals; Dimerization; Dimers; Genetic Diseases, Inborn - enzymology; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - pathology; Genetic mutation; GTP Phosphohydrolases - chemistry; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; GTP-Binding Proteins; Guanosine Diphosphate - chemistry; Guanosine Diphosphate - metabolism; Hereditary spastic paraplegia; Humans; Membrane Fusion - genetics; Membrane Proteins; Membranes; Models, Molecular; Mutation; Neurons; Nucleotides; Paraparesis, Spastic - enzymology; Paraparesis, Spastic - genetics; Paraparesis, Spastic - pathology; Protein Binding; Protein Multimerization; Protein Structure, Quaternary; Protein Structure, Tertiary; Proteins; Schoenlein Henoch purpura; Structure-Activity Relationship
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1012792108

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.