bioRxiv preprint doi: https://doi.org/10.1101/561795; this version posted February 28, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism Nicholas G. Fox1,4, Xiaodi Yu2,4, Xidong Feng2, Henry J. Bailey1, Alain Martelli3, Joseph F. Nabhan3, Claire Strain-Damerell1, Christine Bulawa3, Wyatt W. Yue1,*, Seungil Han2,* 1Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, UK OX3 7DQ 2Discovery Sciences, Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, United States 3Rare Disease Research Unit, Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA, 02139, United States 4These authors contributed equally. *Correspondence should be addressed to Wyatt W. Yue,
[email protected] Seungil Han,
[email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/561795; this version posted February 28, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Iron-sulfur clusters (ISC) are essential in all life forms and carry out many crucial cellular functions. The core machinery for de novo ISC biosynthesis, located in the mitochondria matrix, is a five- protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP.