Ishikawa Haruto, Kato Michiko, Hori Hiroshi, Ishimori Koichiro, Kirisako Takayoshi, Tokunaga Fuminori, Iwai Kazuhiro
Department of Molecular Cell Biology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
Mol Cell. 2005 Jul 22;19(2):171-81. doi: 10.1016/j.molcel.2005.05.027.
Iron regulatory protein 2 (IRP2), a regulator of iron metabolism, is modulated by ubiquitination and degradation. We have shown that IRP2 degradation is triggered by heme-mediated oxidation. We report here that not only Cys201, an invariant residue in the heme regulatory motif (HRM), but also His204 is critical for IRP2 degradation. Spectroscopic studies revealed that Cys201 binds ferric heme, whereas His204 is a ferrous heme binding site, indicating the involvement of these residues in sensing the redox state of the heme iron and in generating the oxidative modification. Moreover, the HRM in IRP2 has been suggested to play a critical role in its recognition by the HOIL-1 ubiquitin ligase. Although HRMs are known to sense heme concentration by simply binding to heme, the HRM in IRP2 specifically contributes to its oxidative modification, its recognition by the ligase, and its sensing of iron concentration after iron is integrated into heme.
铁调节蛋白2（IRP2）是铁代谢的调节因子，受泛素化和降解作用调控。我们已经表明，IRP2的降解是由血红素介导的氧化作用触发的。我们在此报告，不仅血红素调节基序（HRM）中的不变残基半胱氨酸201，而且组氨酸204对IRP2的降解也至关重要。光谱研究表明，半胱氨酸201结合三价铁血红素，而组氨酸204是二价铁血红素结合位点，这表明这些残基参与感知血红素铁的氧化还原状态并产生氧化修饰。此外，有人提出IRP2中的HRM在其被HOIL-1泛素连接酶识别过程中起关键作用。尽管已知HRM通过简单地结合血红素来感知血红素浓度，但IRP2中的HRM特别有助于其氧化修饰、被连接酶识别以及在铁整合到血红素后对铁浓度的感知。
