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

DOI: 10.1038/s41467-019-09989-y DOI Help

Authors: Nicholas G. Fox (Structural Genomic Consortium, University of Oxford) , Xiaodi Yu (Pfizer Inc.) , Xidong Feng (Pfizer Inc.) , Henry J. Bailey (Structural Genomic Consortium, University of Oxford) , Alain Martelli (Pfizer Inc.) , Joseph F. Nabhan (Pfizer Inc.) , Claire Strain-damerell (Structural Genomics Consortium, University of Oxford) , Christine Bulawa (Pfizer Inc.) , Wyatt W. Yue (University of Oxford) , Seungil Han (Pfizer Inc.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: May 2019
Diamond Proposal Number(s): 21035 , 10619

Open Access Open Access

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.

Journal Keywords: Cryoelectron microscopy; Enzyme mechanisms; SAXS

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS

Documents:
s41467-019-09989-y.pdf