Characterization of erythroferrone structural domains relevant to its iron-regulatory function.
Characterization of erythroferrone structural domains relevant to its iron-regulatory function.
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DOI：
10.1016/j.jbc.2023.105374
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Ganz, Tomas
中科院分区：
文献类型：
--
作者：
Srole, Daniel N.;Jung, Grace;Waring, Alan J.;Nemeth, Elizabeta;Ganz, Tomas
铁向血浆的输送与红细胞生成密切相关，因为这一过程消耗了大部分循环中的血浆铁。作为对出血和其他红系压力的反应，增加的促红细胞生成素通过在红系组织中发育的红细胞前体(红细胞母细胞)刺激激素红铁蛋白(ERFe)的产生。ERFe作用于肝脏，抑制骨形态发生蛋白(BMP)信号转导，从而减少海普西丁的产生。降低循环中的海普西丁浓度，然后允许铁从存储释放，并增加从饮食铁吸收。在进化分析和Alphafold2蛋白复合体建模的指导下，我们使用靶向Erfe突变、缺失和合成Erfe片段，以及基于细胞的生物检测和表面等离子共振来探索生物活性和BMP结合所需的结构特征。我们定义了ERFE活性结构域和多种共同作用的结构特征来捕获BMP配体。特别是，疏水螺旋片段81到86，特别是N-末端高度保守的色氨酸W82对于Erfe生物活性是必不可少的，Alphafold2建模将W82放置在其配体BMP2、BMP6和BMP2/6异二聚体的两个色氨酸之间，这种相互作用类似于将BMPs与其同源受体结合的相互作用。最后，我们确定阳离子区域96-107和球形肿瘤坏死因子α样结构域186-354是Erfe多聚化的结构决定因素，它增加了Erfe对BMP配体的亲和力。总而言之，我们的结果为Erfe介导的BMP信号抑制在红系应激反应中的作用提供了进一步的见解。
Iron delivery to the plasma is closely coupled to erythropoiesis, the production of red blood cells, as this process consumes most of the circulating plasma iron. In response to hemorrhage and other erythropoietic stresses, increased erythropoietin stimulates the production of the hormone erythroferrone (ERFE) by erythrocyte precursors (erythroblasts) developing in erythropoietic tissues. ERFE acts on the liver to inhibit bone morphogenetic protein (BMP) signaling and thereby decrease hepcidin production. Decreased circulating hepcidin concentrations then allow the release of iron from stores and increase iron absorption from the diet. Guided by evolutionary analysis and Alphafold2 protein complex modeling, we used targeted ERFE mutations, deletions, and synthetic ERFE segments together with cell-based bioassays and surface plasmon resonance to probe the structural features required for bioactivity and BMP binding. We define the ERFE active domain and multiple structural features that act together to entrap BMP ligands. In particular, the hydrophobic helical segment 81 to 86 and specifically the highly conserved tryptophan W82 in the N-terminal region are essential for ERFE bioactivity and Alphafold2 modeling places W82 between two tryptophans in its ligands BMP2, BMP6, and the BMP2/6 heterodimer, an interaction similar to those that bind BMPs to their cognate receptors. Finally, we identify the cationic region 96-107 and the globular TNFα-like domain 186-354 as structural determinants of ERFE multimerization that increase the avidity of ERFE for BMP ligands. Collectively, our results provide further insight into the ERFE-mediated inhibition of BMP signaling in response to erythropoietic stress.
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