A key protein that helps mitochondria divide is a nonfunctional enzyme, Richter et al. show.
Mitochondria are continually fusing and breaking apart. The protein Drp1 cleaves the organelles. After attaching to a mitochondrion, Drp1 polymerizes to form a molecular noose that tightens and cuts the organelle in two. Two related proteins, MiD49 and MiD51, serve as Drp1’s receptors on the mitochondrial surface. The sequences of MiD49 and MiD51 show few similarities to those of other proteins, and they lack any telling domains or motifs that might reveal how they function.
Richter et al. determined the crystal structure of the cytosolic portion of MiD51 and identified a fold that places the protein in the nucleotidyltransferase superfamily. Members of this clan latch onto nucleotides such as GTP and pass them to a substrate. Because Drp1 is a GTPase, the researchers wondered whether MiD51 was handing off GTP to its partner. However, neither GTP nor ATP bound to MiD51.
On the other hand, the researchers found that MiD51 could bind GDP and ADP, yet these interactions weren’t necessary for mitochondrial fission. Nucleotidyltransferases carry a characteristic stretch of amino acids in their active site. All but one of these amino acids is missing from MiD51, indicating that the protein does not catalyze reactions. Instead, a region in MiD51 that is not usually found in other nucleotidyltransferases helps assemble the Drp1 molecular noose. When Richter et al. mutated this region, MiD51 was unable to connect to Drp1 and promote mitochondrial fission.
The results suggest that MiD51 is a pseudoenzyme that reuses its nucleotidyltransferase fold as an assembly platform. Why MiD51 binds GDP and ADP is unclear, but one possibility is that they regulate the GTPase activity of Drp1.
Text by Mitch Leslie