Zinc mediates the interaction between ceruloplasmin and apo-transferrin for the efficient transfer of Fe(III) ions.
Zinc mediates the interaction between ceruloplasmin and apo-transferrin for the efficient transfer of Fe(III) ions.
复制标题
锌介导铜蓝蛋白和脱铁转铁蛋白之间的相互作用，以实现 Fe(III) 离子的有效转移。
DOI：
10.1093/mtomcs/mfab065
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Yamamura T.
中科院分区：
文献类型：
--
作者：
Sakajiri T;Nakatsuji M;Teraoka Y;Furuta K;Ikuta K;Shibusa K;Sugano E;Tomita H;Inui T;Yamamura T.
从细胞输出的铁（II）可能通过铜蓝蛋白（CP）等多铜氧化铁酶（MCF）氧化为铁（III），从而有效地与血浆铁运输蛋白转铁蛋白（TF）结合。由于未结合的铁（III）是高度不溶性和反应性的，必须防止其在从MCF转移到TF的过程中释放到血液中。阻止未结合铁（III）释放的可能机制是通过MCF和TF之间的直接相互作用；然而，这一现象的发生仍然存在争议。这项研究旨在揭示这些蛋白之间的相互作用，可能是由锌介导的。使用分光光度法、等温滴定量热法和表面等离子体共振方法，我们发现Zn（II）结合的CP与无铁TF （apo-TF）结合，akd4.2 μM，化学计量CP:TF为2:1。CP和载脂蛋白tf之间复合物的计算模型预测，与CP结合的三个Zn（II）离子中的每一个都进一步与载脂蛋白tf的酸性氨基酸残基结合，起到连接两种蛋白质的交联剂的作用。一个CP分子的结构域4和另一个CP分子的结构域6分别与载脂蛋白tf的N-叶和c -叶的间隙紧密吻合。当两个Fe（III）离子与载子TF结合时，通过TF的构象变化，产生了不同的TF [Fe(III)2TF]与CP分离。在人血浆中，锌缺乏减少了铁（III）2TF的产生，并随之增加了非tf结合铁的产生。我们的研究结果表明，锌可能参与铁在CP和TF之间的转移。
Fe(II) exported from cells is oxidized to Fe(III), possibly by a multicopper ferroxidase (MCF) such as ceruloplasmin (CP), to efficiently bind with the plasma iron transport protein transferrin (TF). As unbound Fe(III) is highly insoluble and reactive, its release into the blood during the transfer from MCF to TF must be prevented. A likely mechanism for preventing the release of unbound Fe(III) is via direct interaction between MCF and TF; however, the occurrence of this phenomenon remains controversial. This study aimed to reveal the interaction between these proteins, possibly mediated by zinc. Using spectrophotometry, isothermal titration calorimetry, and surface plasmon resonance methods, we found that Zn(II)-bound CP bound to iron-free TF (apo-TF) with aKdof 4.2 μM and a stoichiometry CP:TF of ∼2:1. Computational modeling of the complex between CP and apo-TF predicted that each of the three Zn(II) ions that bind to CP further binds to an acidic amino acid residue of apo-TF to play a role as a cross-linker connecting both proteins. Domain 4 of one CP molecule and domain 6 of the other CP molecule fit tightly into the clefts in the N- and C-lobes of apo-TF, respectively. Upon the binding of two Fe(III) ions to apo-TF, the resulting diferric TF [Fe(III)2TF] dissociated from CP by conformational changes in TF. In human blood plasma, zinc deficiency reduced the production of Fe(III)2TF and concomitantly increased the production of non-TF-bound iron. Our findings suggest that zinc may be involved in the transfer of iron between CP and TF.