CRYSTAL STRUCTURES OF MINER 1: THE REDOX-ACTIVE 2FE-2S PROTEIN CAUSATIVE IN WOLF

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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。人Miner 1可溶区的晶体结构解析至2.1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。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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. The crystal structure of the soluble region of human Miner1 was solved to a resolution of 2.1 ¿ (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 Cys3-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. Changes in the pH sensitivity of their cluster stabilities are attributed to significant differences in the electrostatic distribution and surfaces between the two proteins.