4.6 Article

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

期刊

PROTEIN SCIENCE
卷 24, 期 3, 页码 386-394

出版社

WILEY
DOI: 10.1002/pro.2629

关键词

mitochondrial fission; mitochondrial dynamics; MiD49; dynamin-related protein

资金

  1. US DOE
  2. NIH
  3. National Institutes of Health [GM110039]
  4. R. L. Kirschstein National Research Service Award [5F31GM089327]
  5. American Physiological Society William Townsend Porter Pre-doctoral fellowship

向作者/读者索取更多资源

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 angstrom. 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.

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