Structural basis of ferroportin inhibition by minihepcidin PR73.
Structural basis of ferroportin inhibition by minihepcidin PR73.
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DOI：
10.1371/journal.pbio.3001936
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发表时间：
2023-01
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
铁转运蛋白（Fpn）是人类唯一已知的铁输出蛋白，对维持铁稳态至关重要。铁调素是一种内源性肽类激素，它抑制铁输出并促进Fpn的内吞作用，从而抑制Fpn的活性。铁调素缺乏导致血色素沉着症和铁负荷性贫血。先前的研究表明，模拟铁调素前几个残基的小肽，即，迷你铁调素比铁调素更有效。然而，minihepcidins增强抑制的机制仍不清楚。在这里，我们报告的结构，人ferroportin在复杂的minihepcidin，PR 73，模仿前9个残基的hepcidin，在2.7 μ m的整体分辨率。该结构揭示了Fpn和铁调素之间不存在的新的相互作用。我们通过结合和转运试验验证PR 73-Fpn相互作用。这些结果提供了对minihepcidin如何增加抑制效力的见解，并将指导Fpn抑制剂的未来开发。膜铁转运蛋白是人类唯一已知的铁输出蛋白，其被内源性肽激素铁调素抑制。与铁调素模拟肽PR 73结合的人膜铁转运蛋白的结构揭示了在铁调素-膜铁转运蛋白复合物中未见的相互作用，并为PR 73的增强的亲和力提供了理论基础。
Ferroportin (Fpn) is the only known iron exporter in humans and is essential for maintaining iron homeostasis. Fpn activity is suppressed by hepcidin, an endogenous peptide hormone, which inhibits iron export and promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis and iron-loading anemia. Previous studies have shown that small peptides that mimic the first few residues of hepcidin, i.e., minihepcidins, are more potent than hepcidin. However, the mechanism of enhanced inhibition by minihepcidins remains unclear. Here, we report the structure of human ferroportin in complex with a minihepcidin, PR73 that mimics the first 9 residues of hepcidin, at 2.7 Å overall resolution. The structure reveals novel interactions that were not present between Fpn and hepcidin. We validate PR73-Fpn interactions through binding and transport assays. These results provide insights into how minihepcidins increase inhibition potency and will guide future development of Fpn inhibitors. Ferroportin is the only known iron exporter in humans, and its suppressed by hepcidin, an endogenous peptide hormone. The structure of human ferroportin bound to the hepcidin mimetic peptide PR73 reveals interactions not seen in the hepcidin-ferroportin complex and provides a rationale for the enhanced affinity of PR73.
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