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FARAFARA Cure FA

Mechanism of activation of the human cysteine desulfurase complex by frataxin

The function of frataxin (FXN) has garnered great scientific interest since its depletion was linked to Friedreich's ataxia (FRDA). FXN has been shown to be necessary for iron-sulfur (Fe-S) cluster biosynthesis and proper mitochondrial function. Although previous studies show that FXN stimulates the activity of this assembly complex, the mechanism of FXN activation is poorly understood. In this study, a radiolabeling assay and stopped-flow kinetics are used to establish that FXN is functionally linked to the mobile S-transfer loop cysteine of NFS1. The results support key roles for this essential cysteine residue in substrate binding, as a general acid to advance the Cys-quinonoid PLP intermediate, as a nucleophile to form an NFS1 persulfide, and as a sulfur delivery agent to generate a persulfide species on the Fe-S scaffold protein ISCU2. FXN specifically accelerates each of these individual steps in the mechanism. The authors propose an architectural switch model explains why the human Fe-S assembly system has low inherent activity and requires activation, the connection between the functional mobile S-transfer loop cysteine and FXN binding, and why the prokaryotic system does not require a similar FXN-based activation. Together, these results provide mechanistic insights into the allosteric-activator role of FXN and suggest new strategies to replace FXN function in the treatment of FRDA.

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About the Author

Jen Farmer

Jen Farmer

Executive Director

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