Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Nicholas G. Fox, Xiaodi Yu, Xidong Feng, Henry J. Bailey, Alain Martelli, Joseph F. Nabhan, Claire Strain-Damerell, Christine Bulawa, Wyatt W. Yue () and Seungil Han ()
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Nicholas G. Fox: University of Oxford
Xiaodi Yu: Discovery Sciences, Worldwide Research and Development, Pfizer Inc.
Xidong Feng: Discovery Sciences, Worldwide Research and Development, Pfizer Inc.
Henry J. Bailey: University of Oxford
Alain Martelli: Rare Disease Research Unit, Worldwide Research and Development, Pfizer Inc.
Joseph F. Nabhan: Rare Disease Research Unit, Worldwide Research and Development, Pfizer Inc.
Claire Strain-Damerell: University of Oxford
Christine Bulawa: Rare Disease Research Unit, Worldwide Research and Development, Pfizer Inc.
Wyatt W. Yue: University of Oxford
Seungil Han: Discovery Sciences, Worldwide Research and Development, Pfizer Inc.

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: Abstract The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), 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. Deficiency in FXN leads to the loss-of-function neurodegenerative disorder Friedreich’s ataxia (FRDA). Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. Our structure reveals how FXN facilitates ISC production through stabilizing key loop conformations of NFS1 and ISCU at the protein–protein interfaces, and suggests how FRDA clinical mutations affect complex formation and FXN activation.

Date: 2019
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DOI: 10.1038/s41467-019-09989-y

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