title: Iron-sulfur cluster exchange reactions mediated by the human Nfu protein.
abstract: Human Nfu is an iron-sulfur cluster protein that has recently been implicated in multiple mitochondrial dysfunctional syndrome (MMDS1). The Nfu family of proteins shares a highly homologous domain that contains a conserved active site consisting of a CXXC motif. There is less functional conservation between bacterial and human Nfu proteins, particularly concerning their Iron-sulfur cluster binding and transfer roles. Herein, we characterize the cluster exchange chemistry of human Nfu and its capacity to bind and transfer a [2Fe-2S] cluster. The mechanism of cluster uptake from a physiologically relevant [2Fe-2S](GS)4 cluster complex, and extraction of the Nfu-bound iron-sulfur cluster by glutathione are described. Human holo Nfu shows a dimer-tetramer equilibrium with a protein to cluster ratio of 2:1, reflecting the Nfu-bridging [2Fe-2S] cluster. This cluster can be transferred to apo human ferredoxins at relatively fast rates, demonstrating a direct role for human Nfu in the process of [2Fe-2S] cluster trafficking and delivery.
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA.|The Ohio State Biochemistry Program, The Ohio State University, Columbus, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Wachnowsky
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA.|The Biophysics Graduate Program, The Ohio State University, Columbus, USA.
authors.forename: Insiya
authors.initials: I
authors.lastname: Fidai
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA.|The Ohio State Biochemistry Program, The Ohio State University, Columbus, USA.|The Biophysics Graduate Program, The Ohio State University, Columbus, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Cowan
mesh_terms: D020816:Amino Acid Motifs; D001059:Apoproteins / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D005288:Ferredoxins / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000378:metabolism*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013455:Sulfur / Q000378:metabolism*
chemical_list: D001059:Apoproteins; D002352:Carrier Proteins; D005288:Ferredoxins; C426067:NFU1 protein, human; D013455:Sulfur; D007501:Iron; D005978:Glutathione
keywords: Cluster exchange; Iron–sulfur cluster; Metalloprotein; Mitochondrial disease; Nfu