Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2
Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2
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DOI：
10.1016/j.molcel.2005.05.027
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发表时间：
2005-07-22
期刊：
影响因子：
16
通讯作者：
Iwai, K
中科院分区：
文献类型：
--
作者：
Ishikawa, H;Kato, M;Iwai, K
γ铁调节蛋白2（IRP 2）是铁代谢的调节因子，通过泛素化和降解来调节。我们已经表明，IRP 2降解是由血红素介导的氧化引发的。我们在这里报告，不仅Cys 201，在血红素调节基序（HRM）不变的残基，但也His 204是至关重要的IRP 2降解。光谱研究表明，Cys 201结合铁血红素，而His 204是亚铁血红素结合位点，表明这些残基参与感测血红素铁的氧化还原状态和产生氧化修饰。此外，IRP 2中的HRM已被认为在其被HOIL-1泛素连接酶识别中起关键作用。虽然已知HRM通过简单地结合血红素来感测血红素浓度，但IRP 2中的HRM特别有助于其氧化修饰、其被连接酶识别以及其在铁整合到血红素中后感测铁浓度。
yIron 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.