Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis.
Human ferrochelatase, a mitochondrial membrane-associated protein, catalyzes the terminal step of heme biosynthesis by insertion of ferrous iron into protoporphyrin IX. The recently solved x-ray structure of human ferrochelatase identifies a potential binding site for an iron donor protein on the matrix side of the homodimer. Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis. A general regulatory mechanism for mitochondrial iron metabolism is described that defines frataxin involvement in both heme and iron-sulfur cluster biosyntheses. In essence, the distinct binding affinities of holofrataxin to the target proteins, ferrochelatase (heme synthesis) and ISU (iron-sulfur cluster synthesis), allows discrimination between the two major iron-dependent pathways and facilitates targeted heme biosynthesis following down-regulation of frataxin.
Yoon
Taejin
T
Evans Laboratory of Chemistry, Ohio State University, Columbus, Ohio 43210, USA.
Cowan
J A
JA
D001665:Binding Sites; D002151:Calorimetry; D018360:Crystallography, X-Ray; D019281:Dimerization; D015536:Down-Regulation; D005294:Ferrochelatase / Q000737:chemistry* / Q000378:metabolism*; D006418:Heme / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000737:chemistry; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D011524:Protoporphyrins / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D020349:Surface Plasmon Resonance; D013997:Time Factors; D000096923:Frataxin
D005294:Ferrochelatase; D006418:Heme; D007501:Iron; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D011524:Protoporphyrins; D000096923:Frataxin; C028025:protoporphyrin IX