Structural studies of human fission protein FIS1 reveal a dynamic region important for GTPase DRP1 recruitment and mitochondrial fission. J Biol Chem 2022 Dec;298(12):102620
Date
10/23/2022Pubmed ID
36272645Pubmed Central ID
PMC9747602DOI
10.1016/j.jbc.2022.102620Scopus ID
2-s2.0-85143990858 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Fission protein 1 (FIS1) and dynamin-related protein 1 (DRP1) were initially described as being evolutionarily conserved for mitochondrial fission, yet in humans the role of FIS1 in this process is unclear and disputed by many. In budding yeast where Fis1p helps to recruit the DRP1 ortholog from the cytoplasm to mitochondria for fission, an N-terminal "arm" of Fis1p is required for function. The yeast Fis1p arm interacts intramolecularly with a conserved tetratricopeptide repeat core and governs in vitro interactions with yeast DRP1. In human FIS1, NMR and X-ray structures show different arm conformations, but its importance for human DRP1 recruitment is unknown. Here, we use molecular dynamics simulations and comparisons to experimental NMR chemical shifts to show the human FIS1 arm can adopt an intramolecular conformation akin to that observed with yeast Fis1p. This finding is further supported through intrinsic tryptophan fluorescence and NMR experiments on human FIS1 with and without the arm. Using NMR, we observed the human FIS1 arm is also sensitive to environmental changes. We reveal the importance of these findings in cellular studies where removal of the FIS1 arm reduces DRP1 recruitment and mitochondrial fission similar to the yeast system. Moreover, we determined that expression of mitophagy adapter TBC1D15 can partially rescue arm-less FIS1 in a manner reminiscent of expression of the adapter Mdv1p in yeast. These findings point to conserved features of FIS1 important for its activity in mitochondrial morphology. More generally, other tetratricopeptide repeat-containing proteins are flanked by disordered arms/tails, suggesting possible common regulatory mechanisms.
Author List
Egner JM, Nolden KA, Harwig MC, Bonate RP, De Anda J, Tessmer MH, Noey EL, Ihenacho UK, Liu Z, Peterson FC, Wong GCL, Widlansky ME, Hill RBAuthors
Megan C. Harwig Research Scientist II in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinFrancis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Michael E. Widlansky MD Associate Director, Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
DynaminsGTP Phosphohydrolases
Humans
Membrane Proteins
Mitochondrial Dynamics
Mitochondrial Proteins
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
