Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 10, Pages 3976-3981Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1101643108
Keywords
protein structure; membrane remodeling; organelle shaping; spastic paraplegia gene 3A; endoplasmic reticulum network formation
Categories
Funding
- National Basic Research Program of China [2010CB911800]
- Ministry of Science and Technology of the People's Republic of China [2008ZX10001-010]
- National Basic Research Program of China (973 Program [2010CB833702]
- National Natural Science Foundation of China [30971440, 90919009]
- 111 Project of China [B08011]
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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.
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