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Published March 2015 | public
Journal Article Open

Crystal structure and functional analysis of MiD49, a receptor for the mitochondrial fission protein Drp1


Mitochondrial fission requires recruitment of dynamin-related protein 1 (Drp1) to the mitochondrial surface, where assembly leads to activation of its GTP-dependent scission function. MiD49 and MiD51 are two receptors on the mitochondrial outer membrane that can recruit Drp1 to facilitate mitochondrial fission. Structural studies indicated that MiD51 has a variant nucleotidyl transferase fold that binds an ADP co-factor essential for activation of Drp1 function. MiD49 shares sequence homology with MiD51 and regulates Drp1 function. However, it is unknown if MiD49 binds an analogous co-factor. Because MiD49 does not readily crystallize, we used structural predictions and biochemical screening to identify a surface entropy reduction mutant that facilitated crystallization. Using molecular replacement, we determined the atomic structure of MiD49 to 2.4 Å. Like MiD51, MiD49 contains a nucleotidyl transferase domain; however, the electron density provides no evidence for a small-molecule ligand. Structural changes in the putative nucleotide-binding pocket make MiD49 incompatible with an extended ligand like ADP, and critical nucleotide-binding residues found in MiD51 are not conserved. MiD49 contains a surface loop that physically interacts with Drp1 and is necessary for Drp1 recruitment to the mitochondrial surface. Our results suggest a structural basis for the differential regulation of MiD51- versus MiD49-mediated fission.

Additional Information

© 2014 The Protein Society. Received 24 October 2014; Revised 17 December 2014; Accepted 18 December 2014. Article first published online: 14 Jan 2015. The authors acknowledge the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi-Aventis Bioengineering Research Program at Caltech for their generous support of the Molecular Observatory at Caltech. Operations at SSRL are supported by the US DOE and NIH. This wol'k was supported by the National Institutes of Health (GM110039). OCL was supported by a R. L. Kirschstein National Research Service Award (5F31GM089327) and an American Physiological Society William Townsend Porter Pre-doctoral fellowship.

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August 22, 2023
August 22, 2023