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Published March 4, 2014 | Supplemental Material + Accepted Version
Journal Article Open

The Mitochondrial Fission Receptor MiD51 Requires ADP as a Cofactor


Mitochondrial fission requires recruitment of dynamin- related protein 1 (Drp1) to the mitochondrial surface and activation of its GTP-dependent scission function. The Drp1 receptors MiD49 and MiD51 recruit Drp1 to facilitate mitochondrial fission, but their mechanism of action is poorly understood. Using X-ray crystallography, we demonstrate that MiD51 contains a nucleotidyl transferase domain that binds ADP with high affinity. MiD51 recruits Drp1 via a surface loop that functions independently of ADP binding. However, in the absence of nucleotide binding, the recruited Drp1 cannot be activated for fission. Purified MiD51 strongly inhibits Drp1 assembly and GTP hydrolysis in the absence of ADP. Addition of ADP relieves this inhibition and promotes Drp1 assembly into spirals with enhanced GTP hydrolysis. Our results reveal ADP as an essential cofactor for MiD51 during mitochondrial fission.

Additional Information

© 2014 Elsevier Ltd. Received: December 31, 2013; Revised: December 31, 2013 Accepted: January 2, 2014; Published: February 6, 2014. Supplemental Information includes five figures and can be found with this article online at http://dx.doi.org/10.1016/j.str.2014.01.001. We are grateful to Meera Rao for assistance with the GTPase assay and Alasdair McDowell for guidance with EM. We thank the Beckman Foundation at Caltech for support of the EM resource and the Gordon and Betty Moore Foundation and Augoron Institute for support of the Grant Jensen lab microscopy center. We 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 Department of Energy and the National Institutes of Health (NIH). This work was supported by a grant from the NIH (GM062967). O.C.L. was supported by an R. L. Kirschstein National Research Service Award (5F31GM089327) and an American Physiological Society William Townsend Porter predoctoral fellowship. PDB Accession Numbers: 4OAF (native structure), 4OAG (bound to ADP), 4OAH (H201A mutant structure), 4OAI (dimer mutant structure)

Attached Files

Accepted Version - nihms576282.pdf

Supplemental Material - mmc1.pdf


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