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Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes.


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.

SUBMITTER: Bian X 

PROVIDER: S-EPMC3054032 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes.

Bian Xin X   Klemm Robin W RW   Liu Tina Y TY   Zhang Miao M   Sun Sha S   Sui Xuewu X   Liu Xinqi X   Rapoport Tom A TA   Hu Junjie J  

Proceedings of the National Academy of Sciences of the United States of America 20110222 10


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  ...[more]

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