Structural analysis of a trimeric assembly of the mitochondrial dynamin-like GTPase Mgm1

Area of Science:

• Mitochondrial biology
• Membrane fusion mechanisms
• Protein structure and function

Background:

• Inner mitochondrial membrane fusion is crucial for cellular health and relies on dynamin-like GTPases like Mgm1 (yeast) and OPA1 (mammals).
• The precise molecular mechanisms by which these GTPases mediate membrane fusion remain largely unknown.

Purpose of the Study:

• To determine the crystal structure of short Mgm1 (s-Mgm1) from Saccharomyces cerevisiae in complex with GDP.
• To elucidate the structural basis for Mgm1 assembly and its interaction with lipids, providing insights into its role in mitochondrial fusion.

Main Methods:

• X-ray crystallography to determine the 3D structure of s-Mgm1-GDP.
• Biochemical assays and in vivo analyses to validate the functional significance of observed structural features and interactions.

Main Results:

• The crystal structure revealed s-Mgm1 comprises an N-terminal GTPase (G) domain, two helix bundles (HB1, HB2), and a C-terminal lipid-interacting stalk (LIS).
• Mgm1 can form dimers via helix bundle interactions and head-to-tail trimers through G domain and HB2-LIS interactions.
• s-Mgm1 interacts with negatively charged lipids through both its G domain and LIS, suggesting a dual role in membrane targeting and binding.

Conclusions:

• The identified assembly interfaces are critical for Mgm1 function in vivo.
• A model is proposed where Mgm1 membrane targeting via G domain and LIS facilitates in cis assembly, promoting membrane curvature for inner membrane fusion.