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The generation of the tubular network of the endoplasmic reticulum (ER) requires homotypic membrane fusion that is mediated by the dynamin-like, membrane-bound GTPase atlastin (ATL). Here, we have determined crystal structures of the cytosolic segment of human ATL1, which give insight into the mechanism of membrane fusion. The structures reveal a GTPase domain and athree-helix bundle, connected by a linker region. One structure corresponds to a prefusion state, in which ATL molecules in apposing membranes interact through their GTPase domains to form a dimer with the nucleotides bound at the interface. The other structure corresponds to a postfusion state generated after GTP hydrolysis and phosphate release. Compared with the prefusion structure, the three-helix bundles of the two ATL molecules undergo a major conformational change relative to the GTPase domains, which could pull the membranes together. The proposed fusion mechanism is supported by biochemical experiments and fusion assays with wild-type and mutant full-length Drosophila ATL. These experiments also show that membrane fusion is facilitated by the C-terminal cytosolic tails following the two transmembrane segments. Finally, our results show that mutations in ATL1 causing hereditary spastic paraplegia compromise homotypic ER fusion.

Original publication

DOI

10.1073/pnas.1101643108

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

08/03/2011

Volume

108

Pages

3976 - 3981

Keywords

Dimerization, Endoplasmic Reticulum, GTP Phosphohydrolases, GTP-Binding Proteins, Guanosine Triphosphate, Humans, Hydrolysis, Membrane Fusion, Membrane Proteins, Models, Molecular, Mutation, Protein Conformation