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铁反应元件结合蛋白调控中RNA结合与乌头酸酶活性的相互控制：铁硫簇的作用

Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster.

作者信息

Haile D J, Rouault T A, Tang C K, Chin J, Harford J B, Klausner R D

机构信息

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.

出版信息

Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7536-40. doi: 10.1073/pnas.89.16.7536.

DOI:10.1073/pnas.89.16.7536
PMID:1502165
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC49745/
Abstract

Several mechanisms of posttranscriptional gene regulation are involved in regulation of the expression of essential proteins of iron metabolism. Coordinate regulation of ferritin and transferrin receptor expression is produced by binding of a cytosolic protein, the iron-responsive element binding protein (IRE-BP) to specific stem-loop structures present in target RNAs. The affinity of this protein for its cognate RNA is regulated by the cell in response to changes in iron availability. The IRE-BP demonstrates a striking level of amino acid sequence identity to the iron-sulfur (Fe-S) protein mitochondrial aconitase. Moreover, the recombinant IRE-BP has aconitase function. The lability of the Fe-S cluster in mitochondrial aconitase has led us to propose that the mechanism by which iron levels are sensed by the IRE-BP involves changes in an Fe-S cluster in the IRE-BP. In this study, we demonstrate that procedures aimed at altering the IRE-BP Fe-S cluster in vitro reciprocally alter the RNA binding and aconitase activity of the IRE-BP. The changes in the RNA binding of the protein produced in vitro appear to match the previously described alterations of the protein in response to iron availability in the cell. Furthermore, iron manipulation of cells correlates with the activation or inactivation of the IRE-BP aconitase activity. The results are consistent with a model for the posttranslational regulation of the IRE-BP in which the Fe-S cluster is altered in response to the availability of intracellular iron and this, in turn, regulates the RNA-binding activity.

摘要

转录后基因调控的几种机制参与了铁代谢必需蛋白表达的调控。铁蛋白和转铁蛋白受体表达的协同调控是由一种胞质蛋白——铁反应元件结合蛋白（IRE-BP）与靶RNA中存在的特定茎环结构结合产生的。细胞会根据铁可用性的变化来调节这种蛋白与其同源RNA的亲和力。IRE-BP与铁硫（Fe-S）蛋白线粒体乌头酸酶的氨基酸序列具有显著的同一性。此外，重组IRE-BP具有乌头酸酶功能。线粒体乌头酸酶中Fe-S簇的不稳定性使我们提出，IRE-BP感知铁水平的机制涉及IRE-BP中Fe-S簇的变化。在本研究中，我们证明，旨在体外改变IRE-BP Fe-S簇的操作会相互改变IRE-BP的RNA结合和乌头酸酶活性。体外产生的蛋白RNA结合的变化似乎与先前描述的该蛋白在细胞中对铁可用性的反应变化相匹配。此外，对细胞进行铁操作与IRE-BP乌头酸酶活性的激活或失活相关。这些结果与IRE-BP翻译后调控的模型一致，即Fe-S簇会根据细胞内铁的可用性而改变，进而调节RNA结合活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7491/49745/ccd514fe4901/pnas01090-0260-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7491/49745/df5836e9d278/pnas01090-0259-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7491/49745/ccd514fe4901/pnas01090-0260-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7491/49745/df5836e9d278/pnas01090-0259-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7491/49745/ccd514fe4901/pnas01090-0260-b.jpg

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本文引用的文献

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