Crystal Structure of Miner1: The Redox-active 2Fe-2S Protein Causative in Wolfram Syndrome 2
Crystal Structure of Miner1: The Redox-active 2Fe-2S Protein Causative in Wolfram Syndrome 2
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DOI：
10.1016/j.jmb.2009.06.079
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发表时间：
2009-09-11
影响因子：
5.6
通讯作者：
Paddock, Mark L.
中科院分区：
文献类型：
--
作者：
Conlan, Andrea R.;Axelrod, Herbert L.;Paddock, Mark L.
内质网蛋白Miner 1对健康和长寿至关重要。编码Miner 1的CISD 2的错误剪接是Wolfram综合征2（WFS 2）的病因，导致早发性视神经萎缩、糖尿病耳聋和寿命缩短。在基因敲除研究中，CISD 2的破坏会导致加速衰老、失明和肌肉萎缩。在这项工作中，我们的特点是人类Miner 1的可溶性区域。并将其晶体结构解析到2.1埃的分辨率（R因子=17%）。虽然最初被注释为锌指，我们发现，矿工1是一个homodimer窝藏两个氧化还原活性2Fe-2S簇，第一次表明与WFS 2的氧化还原活性FeS蛋白的协会。每个2Fe-2S簇由17个氨基酸片段内的罕见Cys（3）-His基序结合。Miner 1是第一个功能不同的蛋白质，它与最近鉴定的线粒体外膜蛋白paramitoNEET共享NEET折叠。我们报告了Miner 1和mitoNEET的氧化还原电位（E-m）的第一次测量，表明它们在pH 7.5时与E-m类似于0 mV的质子偶联。它们的簇稳定性的pH敏感性的变化归因于两种蛋白质之间的静电分布和表面的显着差异。的结构和生物物理结果进行了讨论，在细胞中的铁硫管理和氧化还原反应的矿工1可能的作用。爱思唯尔有限公司出版
The endoplasmic reticulum protein Miner1 is essential for health and longevity. Mis-splicing of CISD2, which codes for Miner1, is causative in Wolfram Syndrome 2 (WFS2) resulting in early onset optic atrophy, diabetes mellitus deafness and decreased lifespan. In knock-out studies, disruption of CISD2 leads to accelerated aging, blindness and muscle atrophy. In this work, we characterized the soluble region of human Miner1. and solved its crystal structure to a resolution of 2.1 angstrom (R-factor=17%). Although originally annotated as a zinc finger, we show that Miner1 is a homodimer harboring two redox-active 2Fe-2S clusters, indicating for the first time an association of a redox-active FeS protein with WFS2. Each 2Fe-2S cluster is bound by a rare Cys(3)-His motif within a 17 amino acid segment. Miner1 is the first functionally different protein that shares the NEET fold with its recently identified paralog mitoNEET, an outer mitochondrial membrane protein. We report the first measurement of the redox potentials (E-m) of Miner1 and mitoNEET, showing that they are proton-coupled with E-m similar to 0 mV at pH 7.5. Changes in the pH sensitivity of their cluster stabilities are attributed to significant differences in the electrostatic distribution and surfaces between the two proteins. The structural and biophysical results are discussed in relation to possible roles of Miner1 in cellular Fe-S management and redox reactions. Published by Elsevier Ltd.