Lipid interaction of the C terminus and association of the transmembrane segments facilitate atlastin-mediated homotypic endoplasmic reticulum fusion

Tina Y. Liu, Xin Bian, Sha Sun, Xiaoyu Hu, Robin W. Klemm, William A. Prinz, Tom A. Rapoport, Junjie Hu

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

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 Cterminal 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 languageEnglish (US)
Pages (from-to)E2146-E2154
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number32
DOIs
StatePublished - Aug 7 2012
Externally publishedYes

Keywords

  • Content mixing
  • Hereditary spastic paraplegia
  • Membrane perturbation
  • Organelle remodeling
  • Organelle shaping

ASJC Scopus subject areas

  • General

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