Journal
JOURNAL OF CELL BIOLOGY
Volume 215, Issue 5, Pages 621-629Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201609019
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Funding
- China Postdoctoral Science Foundation [2014M550713]
- National Natural Science Foundation of China [81322023, 31225006]
- National Basic Research Program of China (973 Program) [2013CB911103, 2014CB542802]
- National Key Research and Development Program [2016YFA0500201]
- Howard Hughes Medical Institute
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Mitochondria undergo fusion and fission. The merging of outer mitochondrial membranes requires mitofusin (MFN), a dynamin-like GTPase. How exactly MFN mediates membrane fusion is poorly understood. Here, we determined crystal structures of a minimal GTPase domain (MGD) of human MFN1, including the predicted GTPase and the distal part of the C-terminal tail (CT). The structures revealed that a helix bundle (HB) formed by three helices extending from the GTPase and one extending from the CT closely attaches to the GTPase domain, resembling the configuration of bacterial dynamin-like protein. We show that the nucleotide-binding pocket is shallow and narrow, rendering weak hydrolysis and less dependence on magnesium ion, and that association of HB affects GTPase activity. MFN1 forms a dimer when GTP or GDP/BeF3-, but not GDP or other analogs, is added. In addition, clustering of vesicles containing membrane anchored MGD requires continuous GTP hydrolysis. These results suggest that MFN tethers apposing membranes, likely through nucleotide-dependent dimerization.
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