Transferrins function in iron sequestration and iron transport by binding iron tightly and reversibly. Vertebrate transferrins coordinate iron through interactions with two tyrosines, an aspartate, a histidine, and a carbonate anion, and conformational changes that occur upon iron binding and release have been described. Much less is known about the structure and functions of insect transferrin‐1 (Tsf1), which is present in hemolymph and influences iron homeostasis mostly by unknown mechanisms. Amino acid sequence and biochemical analyses have suggested that iron coordination by Tsf1 differs from that of the vertebrate transferrins. Here we report the first crystal structure (2.05 Å resolution) of an insect transferrin. Manduca sexta (MsTsf1) in the holo form exhibits a bilobal fold similar to that of vertebrate transferrins, but its carboxyl‐lobe adopts a novel orientation and contacts with the amino‐lobe. The structure revealed coordination of a single Fe³⁺ ion in the amino‐lobe through Tyr90, Tyr204, and two carbonate anions. One carbonate anion is buried near the ferric ion and is coordinated by four residues, whereas the other carbonate anion is solvent exposed and coordinated by Asn121. Notably, these residues are highly conserved in Tsf1 orthologs. Docking analysis suggested that the solvent exposed carbonate position is capable of binding alternative anions. These findings provide a structural basis for understanding Tsf1 function in iron sequestration and transport in insects as well as insight into the similarities and differences in iron homeostasis between insects and humans.

中文翻译：

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对模式昆虫 Manduca sexta 转铁蛋白-1 的新型铁配位和结构域相互作用的结构洞察

转铁蛋白通过紧密且可逆地结合铁来发挥铁螯合和铁运输的作用。脊椎动物转铁蛋白通过与两个酪氨酸、一个天冬氨酸、一个组氨酸和一个碳酸根阴离子相互作用来协调铁，并且已经描述了铁结合和释放时发生的构象变化。关于昆虫转铁蛋白-1 (Tsf1) 的结构和功能知之甚少，该蛋白存在于血淋巴中，主要通过未知机制影响铁稳态。氨基酸序列和生化分析表明，Tsf1 的铁配位与脊椎动物转铁蛋白的铁配位不同。在这里，我们报告了昆虫转铁蛋白的第一个晶体结构（2.05 Å 分辨率）。全息形式的天蛾（MsTsf1）表现出与脊椎动物转铁蛋白相似的双叶折叠，但其羧基叶采用新的方向并与氨基叶接触。该结构揭示了氨基叶中单个 Fe ^{3+离子通过 Tyr90、Tyr204 和两个碳酸根阴离子的配位。}一个碳酸根阴离子埋藏在三价铁离子附近并由四个残基配位，而另一个碳酸根阴离子暴露在溶剂中并由 Asn121 配位。值得注意的是，这些残基在 Tsf1 直向同源物中高度保守。对接分析表明，暴露于溶剂的碳酸酯位置能够结合替代阴离子。这些发现为理解 Tsf1 在昆虫铁固存和运输中的功能以及深入了解昆虫和人类之间铁稳态的异同提供了结构基础。