Structural insight into the novel iron‐coordination and domain interactions of transferrin‐1 from a model insect, Manduca sexta
Structural insight into the novel iron‐coordination and domain interactions of transferrin‐1 from a model insect, Manduca sexta
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DOI：
10.1002/pro.3999
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发表时间：
2020-11
期刊：
影响因子：
8
通讯作者：
J. Weber;M. Kashipathy;K. Battaile;Eden P. Go;H. Desaire;M. Kanost;S. Lovell;M. Gorman
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文献类型：
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作者：
J. Weber;M. Kashipathy;K. Battaile;Eden P. Go;H. Desaire;M. Kanost;S. Lovell;M. Gorman
转铁蛋白通过与铁紧密结合并可逆地参与铁的螯合和转运。脊椎动物转铁蛋白通过与两个酪氨酸、天冬氨酸、组氨酸和碳酸根阴离子的相互作用来协调铁，并且已经描述了在铁结合和释放时发生的构象变化。关于昆虫转铁蛋白-1（Tsf 1）的结构和功能知之甚少，Tsf 1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，铁协调Tsf 1不同的脊椎动物转铁蛋白。在这里，我们报告的第一个晶体结构（2.05纳米分辨率）的昆虫转铁蛋白。全形体的烟草天蛾（MsTsf 1）表现出类似于脊椎动物转铁蛋白的双叶折叠，但其羧基叶采用了新的取向并与氨基叶接触。该结构揭示了单个Fe 3+离子通过Tyr 90、Tyr 204和两个碳酸根阴离子在氨基叶中的配位。一个碳酸根阴离子被埋在铁离子附近，并由四个残基配位，而另一个碳酸根阴离子是溶剂暴露，并由Asn 121配位。值得注意的是，这些残基在Tsf 1直系同源物中高度保守。对接分析表明，溶剂暴露的碳酸酯位置能够结合替代阴离子。这些发现为理解Tsf 1在昆虫铁螯合和运输中的功能以及深入了解昆虫和人类之间铁稳态的相似性和差异提供了结构基础。
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.