The Structure of the Drp1 Lattice on Membrane

Area of Science:

• Cell Biology
• Structural Biology
• Biochemistry

Background:

• Mitochondrial health depends on membrane fission, primarily mediated by dynamin-related protein 1 (Drp1).
• Previous structural studies faced challenges due to sample heterogeneity, limiting understanding of Drp1's mechanism on membranes.

Purpose of the Study:

• To elucidate the structural basis of mitochondrial membrane fission by determining the cryo-electron microscopy structure of full-length human Drp1 on membrane tubules.
• To understand the conformational states and interactions of Drp1 during mitochondrial fission.

Main Methods:

• Cryo-electron microscopy (cryo-EM) of full-length human Drp1 bound to membrane tubules.
• Reconstruction of Average Subtracted Tubular Regions (RASTR) technique to analyze heterogeneous data.
• Identification and analysis of distinct Drp1 lattice conformations.

Main Results:

• Drp1 forms a locally ordered lattice on membrane tubules, lacking global helical symmetry.
• The Drp1 lattice exhibits conserved dynamin rung-like filament interactions and novel stacked GTPase domain conformations.
• Two distinct Drp1 lattice states were identified, indicating conformational changes around hinge 1.
• Observed Drp1-membrane contacts were linked to the variable domain sequence.

Conclusions:

• The study reveals a stepwise,
• ratchet-like
• mechanism for mitochondrial membrane constriction by Drp1.
• The findings provide critical structural insights into the heterogeneous process of mitochondrial fission.
• This work advances our understanding of the molecular machinery governing mitochondrial dynamics.