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Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2018-01-09 00:00:00 , DOI: 10.1073/pnas.1715842115
Colin H. Lipper 1 , Ola Karmi 2 , Yang Sung Sohn 2 , Merav Darash-Yahana 2 , Heiko Lammert 3, 4, 5, 6 , Luhua Song 7 , Amy Liu 7 , Ron Mittler 7 , Rachel Nechushtai 2 , José N. Onuchic 3, 4, 5, 6 , Patricia A. Jennings 1
Affiliation  

The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1–3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased accumulation of mitochondrial labile iron, as well as increased mitochondrial reactive oxygen production. Taken together, our study suggests that the MiNT protein functions in the same pathway as its homodimeric counterparts (mitoNEET and NAF-1), and could be a key player in this pathway within the mitochondria. As such, it represents a target for anticancer or antidiabetic drug development.

中文翻译:

人类单体NEET蛋白MiNT的结构及其在调节癌细胞中铁和活性氧中的作用

NEET家族是一类相对较新的三类相关[2Fe-2S]蛋白(CISD1-3),对人类健康和疾病至关重要。尽管人们对CISD1(mitoNEET)和CISD2(NAF-1)的同二聚体基因产物的兴趣不断增长,但线粒体CISD3蛋白的重要性直到最近才在癌症中得到认可。CISD3基因编码包含两个[2Fe-2S] CDGSH基序的单体蛋白,我们将其称为线粒体内部NEET蛋白(MiNT)。它以伪对称折叠折叠,该折叠在一侧提供了疏水基序,在相对的表面上提供了相对亲水的表面。有趣的是,如分子动力学模拟所示,该蛋白质显示出明显的不对称骨架运动,与面对线粒体外膜/内质网(ER)的胞质侧的同型二聚体不同。但是,像其对应物一样,我们的生物学研究表明,敲除MiNT会导致线粒体不稳定铁的积累增加,以及线粒体活性氧的产生增加。综上所述,我们的研究表明,MiNT蛋白的功能与其同源二聚体(mitoNEET和NAF-1)在相同的途径中发挥作用,并且可能是线粒体内该途径的关键参与者。因此,它代表了抗癌或抗糖尿病药物开发的目标。以及增加线粒体活性氧的产生。综上所述,我们的研究表明,MiNT蛋白的功能与其同源二聚体(mitoNEET和NAF-1)在相同的途径中发挥作用,并且可能是线粒体内该途径的关键参与者。因此,它代表了抗癌或抗糖尿病药物开发的目标。以及增加线粒体活性氧的产生。综上所述,我们的研究表明,MiNT蛋白的功能与其同源二聚体(mitoNEET和NAF-1)在相同的途径中发挥作用,并且可能是线粒体内该途径的关键参与者。因此,它代表了抗癌或抗糖尿病药物开发的目标。
更新日期:2018-01-10
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