Structural and Molecular Characterization of Iron-sensing Hemerythrin-like Domain within F-box and Leucine-rich Repeat Protein 5 (FBXL5)
Structural and Molecular Characterization of Iron-sensing Hemerythrin-like Domain within F-box and Leucine-rich Repeat Protein 5 (FBXL5)
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DOI：
10.1074/jbc.m111.308684
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发表时间：
2012-03-02
影响因子：
4.8
通讯作者：
Bruick, Richard K.
中科院分区：
文献类型：
--
作者：
Thompson, Joel W.;Salahudeen, Ameen A.;Bruick, Richard K.
哺乳动物细胞通过感知生物可利用铁水平的变化并促进适应性反应来维持铁稳态。 FBXL5 是 E3 泛素连接酶复合物的一个亚基，可介导铁调节蛋白 2 的稳定性，铁调节蛋白 2 是参与铁代谢的多个基因的重要转录后调节因子。 FBXL5 的稳定性以铁和氧响应方式进行调节，具体取决于其 N 末端结构域的存在。在这里，我们展示了 FBXL5 N 末端的原子结构，这是一种以前在哺乳动物蛋白质中未观察到的类似血红蛋白的 α 螺旋束折叠。该结构域的核心采用了其二铁中心的组装和传感特性所必需的不寻常的氨基酸种类。这些调控特征控制着 FBXL5 蛋白酶体降解所需的映射序列的可及性。配体响应性血红蛋白结构域的详细分子和结构表征提供了对 FBXL5 作为独特哺乳动物代谢传感器的机制的深入了解。
Mammalian cells maintain iron homeostasis by sensing changes in bioavailable iron levels and promoting adaptive responses. FBXL5 is a subunit of an E3 ubiquitin ligase complex that mediates the stability of iron regulatory protein 2, an important posttranscriptional regulator of several genes involved in iron metabolism. The stability of FBXL5 is regulated in an iron- and oxygen-responsive manner, contingent upon the presence of its N-terminal domain. Here we present the atomic structure of the FBXL5 N terminus, a hemerythrin-like alpha-helical bundle fold not previously observed in mammalian proteins. The core of this domain employs an unusual assortment of amino acids necessary for the assembly and sensing properties of its diiron center. These regulatory features govern the accessibility of a mapped sequence required for proteasomal degradation of FBXL5. Detailed molecular and structural characterization of the ligand-responsive hemerythrin domain provides insights into the mechanisms by which FBXL5 serves as a unique mammalian metabolic sensor.