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The homotypic fusion of endoplasmic reticulum (ER) membranes is mediated by atlastin (ATL), which consists of an N-terminal cytosolic domain containing a GTPase module and a three-helix bundle followed by two transmembrane (TM) segments and a C-terminal tail (CT). Fusion depends on a GTP hydrolysis-induced conformational change in the cytosolic domain. Here, we show that the CT and TM segments also are required for efficient fusion and provide insight into their mechanistic roles. The essential feature of the CT is a conserved amphipathic helix. A synthetic peptide corresponding to the helix, but not to unrelated amphipathic helices, can act in trans to restore the fusion activity of tailless ATL. The CT promotes vesicle fusion by interacting directly with and perturbing the lipid bilayer without causing significant lysis. The TM segments do not serve as mere membrane anchors for the cytosolic domain but rather mediate the formation of ATL oligomers. Point mutations in either the C-terminal helix or the TMs impair ATL's ability to generate and maintain ER morphology in vivo. Our results suggest that protein-lipid and protein-protein interactions within the membrane cooperate with the conformational change of the cytosolic domain to achieve homotypic ER membrane fusion.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





E2146 - E2154


Amino Acid Sequence, Animals, Circular Dichroism, Drosophila Proteins, Drosophila melanogaster, Electrophoresis, Polyacrylamide Gel, Endoplasmic Reticulum, Escherichia coli, Fluoresceins, Fluorescence Resonance Energy Transfer, GTP Phosphohydrolases, Gene Components, Humans, Immunoprecipitation, Lipid Metabolism, Liposomes, Membrane Fusion, Microscopy, Fluorescence, Models, Molecular, Molecular Sequence Data, Species Specificity, Yeasts