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铁调素结合铁转运蛋白的结构揭示铁稳态机制
2020-08-21 19:25

美国加州大学旧金山分校Aashish Manglik、程亦凡等研究人员合作利用铁调素结合铁转运蛋白的结构揭示出铁稳态机制。相关论文于2020年8月19日在线发表于《自然》。

研究人员解析了脂质纳米圆盘中铁转运蛋白的冷冻电镜(cryo-EM)结构,包括载脂蛋白状态以及与钴、铁模拟物和铁调素的复合物。这些结构和伴随的分子动力学模拟确定了铁转运蛋白的N-和C-域内的两个金属结合位点。铁调素以向外开放的构型结合铁转运蛋白,并完全阻塞铁外排途径以抑制转运。铁调素的羧基末端直接与铁转运蛋白C结构域中的二价金属接触。

研究人员进一步表明,铁调素结合至铁转运蛋白与铁结合耦合,并且在铁存在下铁调素亲和力增加80倍。这些结果提出了铁转运蛋白的铁调素调节模型,其中仅铁负载的铁转运蛋白分子被靶向降解。更广泛地讲,研究人员在结构和功能上的了解很可能使铁稳态中的铁调素-铁转运蛋白轴更具针对性。

据介绍,人体内血清铁水平受铁调素铁外转运蛋白铁转运蛋白的作用的严格控制。铁调素通过诱导铁转运蛋白內吞和降解来调节铁的吸收和再循环。铁转运蛋白的异常活动可导致铁超负荷疾病,例如血色素沉着病或铁限制性贫血。

附:英文原文

Title: Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms

Author: Christian B. Billesblle, Caleigh M. Azumaya, Rachael C. Kretsch, Alexander S. Powers, Shane Gonen, Simon Schneider, Tara Arvedson, Ron O. Dror, Yifan Cheng, Aashish Manglik

Issue&Volume: 2020-08-19

Abstract: The serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing ferroportin internalization and degradation1. Aberrant ferroportin activity can lead to diseases of iron overload, such as hemochromatosis, or iron limitation anemias2. Here, we determined cryogenic electron microscopy (cryo-EM) structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with cobalt, an iron mimetic, and hepcidin. These structures and accompanying molecular dynamics simulations identify two metal binding sites within the N- and C-domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway to inhibit transport. The carboxy-terminus of hepcidin directly contacts the divalent metal in the ferroportin C-domain. We further show that hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a model for hepcidin regulation of ferroportin, where only iron loaded ferroportin molecules are targeted for degradation. More broadly, our structural and functional insights are likely to enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.

DOI: 10.1038/s41586-020-2668-z

Source: https://www.nature.com/articles/s41586-020-2668-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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