Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes |
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Authors: | Bian Xin Klemm Robin W Liu Tina Y Zhang Miao Sun Sha Sui Xuewu Liu Xinqi Rapoport Tom A Hu Junjie |
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Affiliation: | Department of Genetics and Cell Biology, College of Life Sciences, and Tianjin Key Laboratory of Protein Sciences, Nankai University, Tianjin 300071, China. |
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Abstract: | 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. |
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Keywords: | protein structure membrane remodeling organelle shaping spastic paraplegia gene 3A endoplasmic reticulum network formation |
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