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M600582200v1
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Papers In Press, published online ahead of print March 9, 2006
J. Biol. Chem, 10.1074/jbc.M600582200
Submitted on January 19, 2006
Revised on March 8, 2006
Accepted on March 9, 2006

Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU in iron-sulfur cluster assembly

Kuanyu Li, Wing-Hang Tong, Robert M. Hughes, and Tracey A. Rouault

NIH, NICHD, NIH, Bethesda, MD 20892

Corresponding Author: rouault{at}mail.nih.gov

Iron-sulfur clusters are prosthetic groups composed of sulfur and iron that are found in respiratory chain complexes and numerous enzymes. Iron-sulfur clusters are synthesized in a multi-step process that utilizes cysteine desulfurases, scaffold proteins, chaperones, and iron donors. Assembly of iron-sulfur clusters occurs in the mitochondrial matrix of mammalian cells, but cytosolic isoforms of three major mammalian iron-sulfur cluster assembly components have been found, raising the possibility that de novo iron-sulfur cluster biogenesis also occurs in cytosol. The human cysteine desulfurase, ISCS, has two isoforms, one of which targets to the mitochondria, whereas the other less abundant form is cytosolic and nuclear. The open-reading frame of cytosolic mammalian ISCS begins at the second AUG of the transcript and lacks mitochondrial targeting information. Yeast complementation experiments have suggested that the human cytosolic ISCS isoform (c-ISCS) cannot be functional. To evaluate function of c-ISCS, we overexpressed the human cytosolic ISCS in yeast Pichia pastoris, and showed that the cytosolic form of ISCS is an active cysteine desulfurase that covalently binds 35S acquired from desulfuration of radiolabeled cysteine. Human cytosolic ISCS dimerized as efficiently as bacterial ISCS and formed a complex in vitro with over-expressed cytosolic human ISCU. When incubated with iron regulatory protein 1, cysteine and iron, the cytosolic forms of ISCS and ISCU facilitated efficient formation of a [4Fe-4S] cluster on IRP1. Thus, the cytosolic form of ISCS is a functional cysteine desulfurase that can collaborate with cytosolic ISCU to promote de novo iron-sulfur cluster formation.


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