Bian, XinKlemm, Robin W.Liu, Tina Y.Zhang, MiaoSun, ShaSui, XuewuLiu, XinqiRapoport, Tom A.Hu, Junjie2019-10-142011Bian, X., R. W. Klemm, T. Y. Liu, M. Zhang, S. Sun, X. Sui, X. Liu, T. A. Rapoport, and J. Hu. 2011. “Structures of the Atlastin GTPase Provide Insight into Homotypic Fusion of Endoplasmic Reticulum Membranes.” Proceedings of the National Academy of Sciences 108 (10): 3976–81. doi:10.1073/pnas.1101643108.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41543125The 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.en-USJournal Article2019-10-1410.1073/pnas.1101643108