Recent progress in structure-function analyses of Nramp proton-dependent metal-ion transporters
Recent progress in structure-function analyses of Nramp proton-dependent metal-ion transporters
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DOI：
10.1139/o06-193
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发表时间：
2006-12-01
影响因子：
2.9
通讯作者：
Cellier, M. F. M.
中科院分区：
文献类型：
--
作者：
Courville, P.;Chaloupka, R.;Cellier, M. F. M.
天然抗性相关巨噬细胞蛋白（Nramp）同系物形成质子偶联转运蛋白家族，其促进二价金属离子（Me 2+，包括Mn 2+、Fe 2+、Co2+和Cd 2+）的细胞吸收。Nramp或溶质载体11（SLC 11）家族在真核生物和细菌中是保守的。人类和啮齿类动物表达2种与铁紊乱和免疫疾病相关的paradox基因。NRAMP 1（SLC 11 A1）蛋白对专职吞噬细胞具有特异性，并从吞噬体中挤出Me 2+以防御摄入的微生物; NRAMP 1基因的多态性与各种免疫疾病相关。NRAMP 2的几种亚型（SLC 11 A2、DMT 1、DCT 1）在再循环内体中或特别是在肠和肾中的上皮细胞的顶膜处普遍表达，并且可以导致铁过载，而损害NRAMP 2功能的突变导致一种形式的先天性小细胞低色素性贫血。结构-功能研究，使用各种实验模型，和诱变方法已经开始揭示Nramp的整体跨膜组织，一些功能上重要的跨膜片段（TMS），以及一个不寻常的机制耦合Me 2+和质子H+运输。所使用的方法包括酵母基因敲除菌株的功能互补，在非洲爪蟾卵母细胞的电生理学分析，和运输试验，使用哺乳动物和细菌细胞和直接和间接测量SLC 11转运蛋白的特性。这些互补的研究使得TMS 1和6能够被鉴定为Me 2+和H+共转运的关键结构片段，并将有助于更深入地了解Nramp转运机制及其对人类健康和疾病中Me 2+稳态的贡献。
The natural resistance-associated macrophage protein (Nramp) homologs form a family of proton-coupled transporters that facilitate the cellular absorption of divalent metal ions (Me2+, including Mn2+, Fe2+, Co2+, and Cd2+). The Nramp, or solute carrier 11 (SLC11), family is conserved in eukaryotes and bacteria. Humans and rodents express 2 parologous genes that are associated with iron disorders and immune diseases. The NRAMP1 (SLC11A1) protein is specific to professional phagocytes and extrudes Me2+ from the phagosome to defend against ingested microbes; polymorphisms in the NRAMP1 gene are associated with various immune diseases. Several isoforms of NRAMP2 (SLC11A2, DMT1, DCT1) are expressed ubiquitously in recycling endosomes or specifically at the apical membrane of epithelial cells in intestine and kidneys, and can contribute to iron overload, whereas mutations impairing NRAMP2 function cause a form of congenital microcytic hypochromic anemia. Structure-function studies, using various experimental models, and mutagenesis approaches have begun to reveal the overall transmembrane organization of Nramp, some of the transmembrane segments (TMS) that are functionally important, and an unusual mechanism coupling Me2+ and proton H+ transport. The approaches used include functional complementation of yeast knockout strains, electrophysiology analyses in Xenopus oocytes, and transport assays that use mammalian and bacterial cells and direct and indirect measurements of SLC11 transporter properties. These complementary studies enabled the identification of TMS1 and 6 as crucial structural segments for Me2+ and H+ symport, and will help develop a deeper understanding of the Nramp transport mechanism and its contribution to Me2+ homeostasis in human health and diseases.