Sequences flanking the transmembrane segments facilitate mitochondrial localization and membrane fusion by mitofusin

Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):E9863-E9872. doi: 10.1073/pnas.1708782114. Epub 2017 Nov 1.


Mitochondria constantly divide and fuse. Homotypic fusion of the outer mitochondrial membranes requires the mitofusin (MFN) proteins, a family of dynamin-like GTPases. MFNs are anchored in the membrane by transmembrane (TM) segments, exposing both the N-terminal GTPase domain and the C-terminal tail (CT) to the cytosol. This arrangement is very similar to that of the atlastin (ATL) GTPases, which mediate fusion of endoplasmic reticulum (ER) membranes. We engineered various MFN-ATL chimeras to gain mechanistic insight into MFN-mediated fusion. When MFN1 is localized to the ER by TM swapping with ATL1, it functions in the maintenance of ER morphology and fusion. In addition, an amphipathic helix in the CT of MFN1 is exchangeable with that of ATL1 and critical for mitochondrial localization of MFN1. Furthermore, hydrophobic residues N-terminal to the TM segments of MFN1 play a role in membrane targeting but not fusion. Our findings provide important insight into MFN-mediated membrane fusion.

Keywords: endoplasmic reticulum; membrane fusion; membrane targeting; mitochondria; mitofusin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Endoplasmic Reticulum / metabolism
  • GTP Phosphohydrolases / metabolism
  • GTP-Binding Proteins / chemistry*
  • GTP-Binding Proteins / metabolism*
  • Membrane Fusion / physiology*
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism*
  • Microscopy, Fluorescence
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / chemistry*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Membranes / chemistry
  • Mitochondrial Membranes / metabolism
  • Models, Molecular
  • Protein Conformation
  • Sequence Alignment
  • Yeasts


  • Membrane Proteins
  • Mitochondrial Membrane Transport Proteins
  • ATL1 protein, human
  • GTP Phosphohydrolases
  • GTP-Binding Proteins