DNM1L mediates fission of mitochondria and peroxisomes, and dysfunction of DNM1L has been implicated in several neurological disorders, such as Alzheimer's, Parkinson's and Huntington's disease. To study the molecular basis of mitochondrial remodelling, we determined the crystal structure of DNM1L that is comprised of a GTPase domain, a BSE and a stalk. DNM1L assembled via a central stalk interface, and mutations in this interface disrupted dimerization and interfered with membrane binding and mitochondrial targeting. Two sequence stretches at the tip of the stalk were shown to be required for ordered assembly of DNM1L on membranes and its function in mitochondrial fission. In the crystals, DNM1L dimers further assembled via a second, previously undescribed, stalk interface to form a linear filament. Mutations in this interface interfered with liposome tubulation and mitochondrial remodelling. Based on these results and electron microscopy reconstructions, we proposed an oligomerization model for DNM1L which differs from that of dynamin and might be adapted to the remodelling of mitochondria.
Fröhlich C., Grabiger S., Schwefel D., Faelber K., Rosenbaum E., Mears J., Rocks O., Daumke O. (2013) Structural insights into oligomerization and mitochondrial remodelling of dynamin 1-like protein. EMBO J 32(9):1280-92.
Researcher in my group
Chris Fröhlich (PhD 2013)
Jason Mears (Case Western University), Oliver Rocks (MDC)
Figure 1: Crystal structure of the DNM1L dimer.
Figure 2: (a) Comparison of the proposed models for the DNM1L (left) and dynamin (right) oligomers. (b) The proposed arrangement of the DNM1L and dynamin domains in the two oligomers is schematically depicted.