Structural basis of ion transport and inhibition in ferroportin.
Structural basis of ion transport and inhibition in ferroportin.
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离子转运和抑制铁蛋白的结构基础。
DOI：
10.1038/s41467-020-19458-6
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发表时间：
2020-11-10
影响因子：
16.6
通讯作者：
Zhou M
中科院分区：
文献类型：
--
作者：
Pan Y;Ren Z;Gao S;Shen J;Wang L;Xu Z;Yu Y;Bachina P;Zhang H;Fan X;Laganowsky A;Yan N;Zhou M
Ferroportin是一种铁输出者，对于将细胞铁释放到循环中至关重要。铁转运蛋白被肽激素铁调素抑制。在人类中，膜铁转运蛋白的突变导致膜铁转运蛋白疾病，其通常与巨噬细胞中的铁积累和缺铁性贫血的症状相关。在这里，我们提出的ferroportin从灵长类动物菲律宾眼镜猴（TsFpn）的铁调素的存在和不存在下，通过冷冻电子显微镜解决的结构。TsFpn由两个类似蛤壳的结构域组成，并且结构限定了两个金属离子结合位点，每个结构域中一个。这两种结构都处于向外的构象，并且铁调素在两个结构域之间结合并到达离子结合位点之一。功能研究表明TsFpn是一种电中性H+/Fe ~（2+）反向转运蛋白，因此每个Fe ~（2+）的转运与两个H+的反向转运相耦合。扰动任一离子结合位点会损害H+和Fe 2+的耦合运输。这些结果奠定了膜铁转运蛋白与金属离子结合、转运和抑制的结构基础，为膜铁转运蛋白靶向药物干预膜铁转运蛋白疾病提供了蓝图。膜铁转运蛋白是一种铁输出蛋白，是将细胞铁释放到循环中所必需的，并被肽激素铁调素抑制。在这里，作者提出了冷冻电镜结构的ferroportin从灵长类动物菲律宾眼镜猴（TsFpn）与hepcidin和无TsFpn是一个电中性H+ /Fe 2+反向转运蛋白。
Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and hepcidin binds between the two domains and reaches one of the ion binding sites. Functional studies show that TsFpn is an electroneutral H+/Fe2+ antiporter so that transport of each Fe2+ is coupled to transport of two H+ in the opposite direction. Perturbing either of the ion binding sites compromises the coupled transport of H+ and Fe2+. These results establish the structural basis of metal ion binding, transport and inhibition in ferroportin and provide a blueprint for targeting ferroportin in pharmacological intervention of ferroportin diseases. Ferroportin is an iron exporter essential for releasing cellular iron into circulation and is inhibited by a peptide hormone, hepcidin. Here authors present cryo-EM structures of the ferroportin from the primate Philippine tarsier (TsFpn) with and without hepcidin and show that TsFpn is an electroneutral H+ /Fe2+ antiporter.
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影响因子：
48
作者：
Barad BA;Echols N;Wang RY;Cheng Y;DiMaio F;Adams PD;Fraser JS
通讯作者：
Fraser JS
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
64.8
作者：
Bai Y;McCoy JG;Levin EJ;Sobrado P;Rajashankar KR;Fox BG;Zhou M
通讯作者：
Zhou M
影响因子：
16.6
作者：
Deshpande CN;Ruwe TA;Shawki A;Xin V;Vieth KR;Valore EV;Qiao B;Ganz T;Nemeth E;Mackenzie B;Jormakka M
通讯作者：
Jormakka M
影响因子：
4.8
作者：
Abboud, S;Haile, DJ
通讯作者：
Haile, DJ