The structural basis of iron sensing by the human F-box protein FBXL5.
The structural basis of iron sensing by the human F-box protein FBXL5.
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DOI：
10.1002/cbic.201200043
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发表时间：
2012-04-16
期刊：
影响因子：
3.2
通讯作者：
Li, Pingwei
中科院分区：
文献类型：
--
作者：
Shu, Chang;Sung, Min Woo;Stewart, Mikaela D.;Igumenova, Tatyana I.;Tan, Xiangshi;Li, Pingwei
铁是所有生命形式的基本化学元素。它作为参与氧转运、能量代谢和DNA合成的许多蛋白质和酶的辅因子[1，2]。哺乳动物细胞需要维持足够量的铁以支持需要铁作为辅因子的蛋白质的合成。铁通过循环铁转运蛋白运铁蛋白进入细胞[3，4]。负载铁的转铁蛋白与细胞表面转铁蛋白受体结合，导致转铁蛋白的内吞作用和铁货物进入细胞的递送[4]。细胞中过量的铁储存在胞质蛋白铁蛋白中[4]。铁调节蛋白IRP 1和IRP 2通过转铁蛋白受体和铁蛋白表达的翻译后调节来维持铁的稳态[2，5]。在缺铁细胞中，IRP 2被蛋白酶体泛素化和降解。含有F-box和亮氨酸重复序列的蛋白FBXL 5作为细胞溶质铁传感器，通过SKP 1-CUL 1-FBXL 5（SCF）E3泛素连接酶复合物调节IRP 2的泛素化[6，7]。FBXL 5还在细胞溶质中的氧传感中发挥关键作用[6，7]。在小鼠中敲除FBXL 5会由于铁的过量积累而导致胚胎死亡[8]。FBXL 5在其N端含有一个Hemerythrin（Hr）样结构域，在中间含有一个F-box结构域，在C端含有一个富含亮氨酸的重复序列（LRR）结构域。与无脊椎动物和细菌中的铁和氧结合蛋白家族相关的Hr样结构域[9，10]负责铁和氧传感[6，7]。F-box结构域与SKP 1相互作用，SKP 1在SCF E3复合物中充当FBXL 5和Cullin-1之间的桥梁[6，7，11，12]。LRR结构域被提议与底物IRP 2相关联。
Iron is an essential chemical element for all forms of life. It serves as a cofactor for many proteins and enzymes involved in oxygen transport, energy metabolism and DNA synthesis [1, 2]. Mammalian cells need to maintain a sufficient amount of iron to support the synthesis of proteins that require iron as a co-factor. Iron is imported into the cells through the circulating iron transporter transferrin [3, 4]. Iron-loaded transferrin binds to cell surface transferrin receptor, resulting in the endocytosis of transferrin and delivery of the iron cargo into the cells [4]. Excess iron in the cells is stored in the cytosolic protein ferritin [4]. Iron regulatory proteins IRP1 and IRP2 maintain the homeostasis of iron through posttranslational regulation of the expression of transferrin receptor and ferritin [2, 5]. In ironreplete cells IRP2 is ubiquitinated and degraded by the proteasome. The F-box and leucinerich repeat containing protein FBXL5 serves as a cytosolic iron sensor that regulates the ubiquitination of IRP2 by the SKP1-CUL1-FBXL5 (SCF) E3 ubiquitin ligase complex [6, 7]. FBXL5 also plays critical roles in sensing oxygen in the cytosol [6, 7]. Knock out of FBXL5 in mice result in embryonic mortality due to excess accumulation of iron [8].FBXL5 contains a hemerythrin (Hr) like domain at its N-terminus, an F-box-domain in the middle, and a leucine-rich repeat (LRR) domain at the C-terminus. The Hr like domain, which is related to a family of iron and oxygen binding proteins in invertebrates and bacteria [9, 10], is responsible for iron and oxygen sensing [6, 7]. The F-box domain interacts with SKP1, which serves as a bridge between FBXL5 and Cullin-1 in the SCF E3 complex [6, 7, 11, 12]. The LRR domain is proposed to associate with the substrate IRP2.
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DOI：
10.1042/bj20101825
发表时间：
2011-03-15
期刊：
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影响因子：
--
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通讯作者：
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影响因子：
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