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

Oliver C Losón1, Shuxia Meng, Huu Ngo

  • 1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, 91125.

Protein Science : a Publication of the Protein Society
|January 13, 2015
PubMed

Insights

MiD49, a mitochondrial fission receptor, lacks the ADP-binding site found in MiD51, suggesting distinct regulatory mechanisms for Drp1 recruitment and mitochondrial dynamics.

Area of Science:

  • Cell Biology
  • Structural Biology
  • Biochemistry

Background:

  • Mitochondrial fission is crucial for cellular function and relies on dynamin-related protein 1 (Drp1) recruitment.
  • MiD49 and MiD51 are mitochondrial outer membrane receptors that recruit Drp1 to mediate fission.
  • MiD51 binds ADP, activating Drp1, but MiD49's cofactor binding and regulatory mechanism remain unclear.

Purpose of the Study:

  • To determine the atomic structure of MiD49 and elucidate its mechanism of Drp1 recruitment.
  • To investigate whether MiD49 binds a cofactor analogous to the ADP bound by MiD51.
  • To understand the structural basis for differential regulation of mitochondrial fission by MiD49 and MiD51.

Main Methods:

  • Utilized structural predictions and biochemical screening to generate a crystallizable MiD49 mutant.
  • Determined the atomic structure of MiD49 to 2.4 Å resolution using molecular replacement.
  • Analyzed the nucleotide-binding pocket and identified a key surface loop for Drp1 interaction.

Main Results:

  • The MiD49 structure reveals a nucleotidyl transferase domain but lacks electron density for any small-molecule ligand.
  • The putative nucleotide-binding pocket of MiD49 is structurally incompatible with ADP binding, and key residues differ from MiD51.
  • A surface loop on MiD49 directly interacts with Drp1, mediating its recruitment to the mitochondrial surface.

Conclusions:

  • MiD49 does not bind ADP or a similar cofactor, distinguishing its mechanism from MiD51.
  • MiD49's Drp1 recruitment is mediated by a distinct surface loop, independent of nucleotide binding.
  • These findings provide a structural basis for the differential regulation of mitochondrial fission mediated by MiD49 and MiD51.
Keywords:
MiD49dynamin-related proteinmitochondrial dynamicsmitochondrial fission

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