title: [2Fe-2S] cluster transfer in iron-sulfur protein biogenesis.
abstract: 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.
authors.affiliation: Magnetic Resonance Center and Department of Chemistry, University of Florence, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Banci
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.forename: Simone
authors.initials: S
authors.lastname: Ciofi-Baffoni
authors.forename: Rebecca
authors.initials: R
authors.lastname: Del Conte
authors.forename: Ravisekhar
authors.initials: R
authors.lastname: Gadepalli
authors.forename: Maciej
authors.initials: M
authors.lastname: Mikolajczyk
authors.forename: Sara
authors.initials: S
authors.lastname: Neri
authors.forename: Mario
authors.initials: M
authors.lastname: Piccioli
authors.forename: Julia
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D054477:Glutaredoxins / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D013455:Sulfur / Q000378:metabolism*
chemical_list: D001059:Apoproteins; D054477:Glutaredoxins; C489112:ISCA1 protein, human; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D012996:Solutions; D013455:Sulfur; D007501:Iron; D005978:Glutathione
keywords: Fe/S protein maturation; NMR; [2Fe-2S] cluster transfer mechanism; monothiol Grxs
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