Abstract
Iron-sulfur cluster proteins play key roles in a multitude of physiological processes; including gene expression, nitrogen and oxygen sensing, electron transfer, and DNA repair. Biosynthesis of iron-sulfur clusters occurs in mitochondria on iron-sulfur cluster scaffold proteins in the form of [2Fe-2S] cores that are then transferred to apo targets within metabolic or respiratory pathways. The mechanism by which cytosolic Fe-S cluster proteins mature to their holo forms remains controversial. The mitochondrial inner membrane protein Atm1p can transport glutathione-coordinated iron-sulfur clusters, which may connect the mitochondrial and cytosolic iron-sulfur cluster assembly systems. Herein we describe experiments on the yeast Atm1p/ABCB7 exporter that provide additional support for a glutathione-complexed cluster as the natural physiological substrate and a reflection of the endosymbiotic model of mitochondrial evolution. These studies provide insight on the mechanism of cluster transport and the molecular basis of human disease conditions related to ABCB7. Recruitment of MgATP following cluster binding promotes a structural transition from closed to open conformations that is mediated by coupling helices, with MgATP hydrolysis facilitating the return to the closed state.