We propose that eukaryoticcysteine desulfurases are unusual members of the morpheein class ofenzymes that control their activity through their oligomeric state.Overall, the findings support architectural switching as a regulatorymechanism linked to FXN activation of the human Fe–S clusterbiosynthetic complex and provide new opportunities for therapeuticinterventions of the fatal neurodegenerative disease FRDA. Here, FXN is linked to Friedreich ataxia.