Identification of a ubiquitin-ligase which recognizes oxidized proteins.

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We have been shown that the RNA binding protein, iron regulatory protein 2 (IRP2), which is known to be a master regulator of iron metabolism, is degraded by proteasome in the presence of iron. We have also shown that oxidation of the protein by iron creates the signal for the ubiquitination of IRP2 prior to its degradation. In the present study, we tried to identify the mode of iron binding to IRP2, the oxidative modification of IRP2 provoked by iron and ubiquitin-ligase (E3) recognizing oxidized IRP2. We identified that aluminum stabilizes IRP2 by inhibiting iron-induced oxidation of the protein competitively, which suggest that iron binding site (s) are present in IRP2 and that aluminum can bind to the iron binding site of IRP2 competitively to iron. Considering that organisms have not been encountered to aluminum during the evolution, they acquired the metal binding site that is highly selective to iron. Now, we are analyzing the exact nature of the iron binding site. Although we have not published yet, we have found that the IDD domain protein, which domain is necessary for the iron-dependent degradation of IRP2, can bind to E3 for IRP2 in an iron-dependent manner. In other word, the IDD domain serves as the site of iron binding, oxidized by iron and recognized by E3 for IRP2. We are currently identifying E3 for IRP2 by using this assay system. Moreover, we have been identified that Familial Parkinson's disease gene product, Parkin, is a ubiquitin-protein ligase together with Professor Y.Mizuno at Juntendo University and Dr. K.Tanaka at Tokyo Metropolitan Institute of Medical Science.