鐵調素結合鐵轉運蛋白的結構揭示鐵穩態機制

鐵調素結合鐵轉運蛋白的結構揭示鐵穩態機制

作者：

小柯機器人

發布時間：2020/8/21 19:25:51

美國加州大學舊金山分校Aashish Manglik、程亦凡等研究人員合作利用鐵調素結合鐵轉運蛋白的結構揭示出鐵穩態機制。相關論文於2020年8月19日在線發表於《自然》。

研究人員解析了脂質納米圓盤中鐵轉運蛋白的冷凍電鏡（cryo-EM）結構，包括載脂蛋白狀態以及與鈷、鐵模擬物和鐵調素的複合物。這些結構和伴隨的分子動力學模擬確定了鐵轉運蛋白的N-和C-域內的兩個金屬結合位點。鐵調素以向外開放的構型結合鐵轉運蛋白，並完全阻塞鐵外排途徑以抑制轉運。鐵調素的羧基末端直接與鐵轉運蛋白C結構域中的二價金屬接觸。

研究人員進一步表明，鐵調素結合至鐵轉運蛋白與鐵結合耦合，並且在鐵存在下鐵調素親和力增加80倍。這些結果提出了鐵轉運蛋白的鐵調素調節模型，其中僅鐵負載的鐵轉運蛋白分子被靶向降解。更廣泛地講，研究人員在結構和功能上的了解很可能使鐵穩態中的鐵調素-鐵轉運蛋白軸更具針對性。

據介紹，人體內血清鐵水平受鐵調素鐵外轉運蛋白鐵轉運蛋白的作用的嚴格控制。鐵調素通過誘導鐵轉運蛋白內吞和降解來調節鐵的吸收和再循環。鐵轉運蛋白的異常活動可導致鐵超負荷疾病，例如血色素沉著病或鐵限制性貧血。

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