Structural basis for recruitment of mitochondrial fission complexes by Fis1

Creators: Zhang, Yan; Chan, David C.

Abstract

Mitochondrial fission controls mitochondrial shape and physiology, including mitochondrial remodeling in apoptosis. During assembly of the yeast mitochondrial fission complex, the outer membrane protein Fis1 recruits the dynamin-related GTPase Dnm1 to mitochondria. Fis1 contains a tetratricopeptide repeat (TPR) domain and interacts with Dnm1 via the molecular adaptors Mdv1 and Caf4. By using crystallographic analysis of adaptor-Fis1 complexes, we show that these adaptors use two helices to bind to both the concave and convex surfaces of the Fis1 TPR domain. Fis1 therefore contains two interaction interfaces, a binding mode that, to our knowledge, has not been observed previously for TPR domains. Genetic and biochemical studies indicate that both binding interfaces are important for binding of Mdv1 and Caf4 to Fis1 and for mitochondrial fission activity in vivo. Our results reveal how Fis1 recruits the mitochondrial fission complex and will facilitate efforts to manipulate mitochondrial fission.

Additional Information

©2007 by the National Academy of Sciences. Edited by Giuseppe Attardi, California Institute of Technology, Pasadena, CA, and approved September 28, 2007 (received for review July 9, 2007). Published online before print November 12, 2007, doi: 10.1073/pnas.0706441104. This article is a PNAS Direct Submission. We thank Dr. J. M. Shaw for providing the GFP–Mdv1 vector, Priscilla Tee for technical assistance, and Erik Griffin (The Johns Hopkins University, Baltimore, MD) and Takumi Koshiba (Kyushu University, Fukuoka, Japan) for some expression constructs. Diffraction data were collected at the Stanford Synchrotron Radiation Laboratory. This work was supported by National Institutes of Health Grants GM062967 and GM083121 (to D.C.C.). Y.Z. was supported by an Elizabeth Ross postdoctoral fellowship. Author contributions: Y.Z. and D.C.C. designed research; Y.Z. performed research; Y.Z. and D.C.C. analyzed data; and Y.Z. and D.C.C. wrote the paper. The authors declare no conflict of interest. Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 2PQN and 2PQR). This article contains supporting information online at www.pnas.org/cgi/content/full/0706441104/DC1.

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