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铁离子通过铁蛋白通道转运的静电和结构基础

Electrostatic and Structural Bases of Fe2+ Translocation through Ferritin Channels.

作者信息

Chandramouli Balasubramanian, Bernacchioni Caterina, Di Maio Danilo, Turano Paola, Brancato Giuseppe

机构信息

From the Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa,

the Istituto Nazionale di Fisica Nucleare (INFN) Sezione di Pisa, Largo Bruno Pontecorvo 3, 56127 Pisa, and.

出版信息

J Biol Chem. 2016 Dec 2;291(49):25617-25628. doi: 10.1074/jbc.M116.748046. Epub 2016 Oct 18.

Abstract

Ferritin molecular cages are marvelous 24-mer supramolecular architectures that enable massive iron storage (>2000 iron atoms) within their inner cavity. This cavity is connected to the outer environment by two channels at C3 and C4 symmetry axes of the assembly. Ferritins can also be exploited as carriers for in vivo imaging and therapeutic applications, owing to their capability to effectively protect synthetic non-endogenous agents within the cage cavity and deliver them to targeted tissue cells without stimulating adverse immune responses. Recently, X-ray crystal structures of Fe-loaded ferritins provided important information on the pathways followed by iron ions toward the ferritin cavity and the catalytic centers within the protein. However, the specific mechanisms enabling Fe uptake through wild-type and mutant ferritin channels is largely unknown. To shed light on this question, we report extensive molecular dynamics simulations, site-directed mutagenesis, and kinetic measurements that characterize the transport properties and translocation mechanism of Fe through the two ferritin channels, using the wild-type bullfrog Rana catesbeiana H' protein and some of its variants as case studies. We describe the structural features that determine Fe translocation with atomistic detail, and we propose a putative mechanism for Fe transport through the channel at the C3 symmetry axis, which is the only iron-permeable channel in vertebrate ferritins. Our findings have important implications for understanding how ion permeation occurs, and further how it may be controlled via purposely engineered channels for novel biomedical applications based on ferritin.

摘要

铁蛋白分子笼是奇妙的24聚体超分子结构,能够在其内腔中大量储存铁(>2000个铁原子)。该内腔通过组装体C3和C4对称轴处的两个通道与外部环境相连。铁蛋白还可被用作体内成像和治疗应用的载体,因为它们能够有效保护笼腔内的合成非内源性物质,并将其递送至靶向组织细胞而不引发不良免疫反应。最近,负载铁的铁蛋白的X射线晶体结构提供了有关铁离子进入铁蛋白腔的途径以及蛋白质内催化中心的重要信息。然而,通过野生型和突变型铁蛋白通道摄取铁的具体机制很大程度上尚不清楚。为了阐明这个问题,我们报告了广泛的分子动力学模拟、定点诱变和动力学测量,以野生型牛蛙Rana catesbeiana H'蛋白及其一些变体为案例研究,表征铁通过两个铁蛋白通道的传输特性和转运机制。我们详细描述了决定铁转运的结构特征,并提出了一种铁通过C3对称轴处通道的推测转运机制,该通道是脊椎动物铁蛋白中唯一的铁通透通道。我们的研究结果对于理解离子渗透如何发生以及进一步如何通过基于铁蛋白的新型生物医学应用中特意设计的通道进行控制具有重要意义。

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