Title: Shaping the tubular ER network
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). 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. We also show that the C-terminal tail (CT) and the transmembrane (TM) segments of ATL 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 directly interacting 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.
Venue: Room143,New Biology Building,THU
Time:June 26(Tuesday), 2012;16:30
Host: Prof. Nieng Yan
Speaker: Junjie Hu Ph.D.
Professor, Department of Genetics and Cell Biology,
College of Life Sciences , Nankai University
2000 B.S. Biochemistry Fudan University, Shanghai, China
2005 Ph.D. Biomedical Science New York University
2008 Postdoctoral Cell Biology Harvard Medical School/HHMI
Other Experience and Professional Memberships
2010-present Academic Committee, “Membrane and Cell Biology” for Biophysical Society of China
2010- Member, Chinese Society for Cell Biology
2009- Member, Biophysical Society of China
2007- Member, American Society for Cell Biology
2007- Member, American Association for the Advancement of Science
Honors
2012 HHMI International Early Career Scientist
