[2Fe-2S] cluster transfer in iron–sulfur protein biogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 17; pp. 6203 - 6208
• Main Authors: Banci, Lucia, Brancaccio, Diego, Ciofi-Baffoni, Simone, Del Conte, Rebecca, Gadepalli, Ravisekhar, Mikolajczyk, Maciej, Neria, Sara, Piccioli, Mario, Winkelmann, Julia
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.04.2014; National Acad Sciences
• Subjects: Apoproteins - chemistry; Apoproteins - metabolism; Binding sites; Biosynthesis; Cells; Chemical equilibrium; Crystal structure; Glutaredoxins - chemistry; Glutaredoxins - metabolism; Glutathione - metabolism; Humans; Iron; Iron - metabolism; Iron sulfur proteins; Iron-Sulfur Proteins - chemistry; Iron-Sulfur Proteins - metabolism; Magnetic Resonance Spectroscopy; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - metabolism; Models, Molecular; Molecules; Phosphates; Physical Sciences; Protein Binding; Protein Structure, Quaternary; Proteins; Scaffolds; Signal detection; Solutions; Spectrophotometry, Ultraviolet; Sulfur; Sulfur - metabolism; Fe/S protein maturation; NMR; [2Fe-2S] cluster transfer mechanism; monothiol Grxs
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1400102111

Monothiol glutaredoxins play a crucial role in iron–sulfur (Fe/S) protein biogenesis. Essentially all of them can coordinate a [2Fe-2S] cluster and have been proposed to mediate the transfer of [2Fe-2S] clusters from scaffold proteins to target apo proteins, possibly by acting as cluster transfer proteins. The molecular basis of [2Fe-2S] cluster transfer from monothiol glutaredoxins to target proteins is a fundamental, but still unresolved, aspect to be defined in Fe/S protein biogenesis. In mitochondria monothiol glutaredoxin 5 (GRX5) is involved in the maturation of all cellular Fe/S proteins and participates in cellular iron regulation. Here we show that the structural plasticity of the dimeric state of the [2Fe-2S] bound form of human GRX5 (holo hGRX5) is the crucial factor that allows an efficient cluster transfer to the partner proteins human ISCA1 and ISCA2 by a specific protein–protein recognition mechanism. Holo hGRX5 works as a metallochaperone preventing the [2Fe-2S] cluster to be released in solution in the presence of physiological concentrations of glutathione and forming a transient, cluster-mediated protein–protein intermediate with two physiological protein partners receiving the [2Fe-2S] cluster. The cluster transfer mechanism defined here may extend to other mitochondrial [2Fe-2S] target proteins.