Tamir Sagi, Paddock Mark L, Darash-Yahana-Baram Merav, Holt Sarah H, Sohn Yang Sung, Agranat Lily, Michaeli Dorit, Stofleth Jason T, Lipper Colin H, Morcos Faruck, Cabantchik Ioav Z, Onuchic Jose' N, Jennings Patricia A, Mittler Ron, Nechushtai Rachel
The Alexander Silberman Life Science Institute and the Wolfson Centre for Applied Structural Biology, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
Biochim Biophys Acta. 2015 Jun;1853(6):1294-315. doi: 10.1016/j.bbamcr.2014.10.014. Epub 2014 Oct 23.
A novel family of 2Fe-2S proteins, the NEET family, was discovered during the last decade in numerous organisms, including archea, bacteria, algae, plant and human; suggesting an evolutionary-conserved function, potentially mediated by their CDGSH Iron-Sulfur Domain. In human, three NEET members encoded by the CISD1-3 genes were identified. The structures of CISD1 (mitoNEET, mNT), CISD2 (NAF-1), and the plant At-NEET uncovered a homodimer with a unique "NEET fold", as well as two distinct domains: a beta-cap and a 2Fe-2S cluster-binding domain. The 2Fe-2S clusters of NEET proteins were found to be coordinated by a novel 3Cys:1His structure that is relatively labile compared to other 2Fe-2S proteins and is the reason of the NEETs' clusters could be transferred to apo-acceptor protein(s) or mitochondria. Positioned at the protein surface, the NEET's 2Fe-2S's coordinating His is exposed to protonation upon changes in its environment, potentially suggesting a sensing function for this residue. Studies in different model systems demonstrated a role for NAF-1 and mNT in the regulation of cellular iron, calcium and ROS homeostasis, and uncovered a key role for NEET proteins in critical processes, such as cancer cell proliferation and tumor growth, lipid and glucose homeostasis in obesity and diabetes, control of autophagy, longevity in mice, and senescence in plants. Abnormal regulation of NEET proteins was consequently found to result in multiple health conditions, and aberrant splicing of NAF-1 was found to be a causative of the neurological genetic disorder Wolfram Syndrome 2. Here we review the discovery of NEET proteins, their structural, biochemical and biophysical characterization, and their most recent structure-function analyses. We additionally highlight future avenues of research focused on NEET proteins and propose an essential role for NEETs in health and disease. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.
一个新的2Fe-2S蛋白家族，即NEET家族，在过去十年中在众多生物体中被发现，包括古细菌、细菌、藻类、植物和人类；这表明其具有进化保守功能，可能由其CDGSH铁硫结构域介导。在人类中，已鉴定出由CISD1-3基因编码的三个NEET成员。CISD1（线粒体NEET，mNT）、CISD2（NAF-1）和植物At-NEET的结构揭示了一种具有独特“NEET折叠”的同二聚体，以及两个不同的结构域：一个β帽和一个2Fe-2S簇结合结构域。发现NEET蛋白的2Fe-2S簇由一种新型的3Cys:1His结构配位，与其他2Fe-2S蛋白相比相对不稳定，这也是NEETs的簇能够转移到脱辅基受体蛋白或线粒体的原因。位于蛋白质表面，NEET的2Fe-2S配位His在其环境变化时会发生质子化，这可能表明该残基具有传感功能。在不同模型系统中的研究表明，NAF-1和mNT在细胞铁、钙和ROS稳态的调节中起作用，并揭示了NEET蛋白在关键过程中的关键作用，如癌细胞增殖和肿瘤生长、肥胖和糖尿病中的脂质和葡萄糖稳态、自噬控制、小鼠寿命以及植物衰老。因此，发现NEET蛋白的异常调节会导致多种健康状况，并且发现NAF-1的异常剪接是神经遗传疾病沃尔弗拉姆综合征2的病因。在这里，我们综述了NEET蛋白的发现、它们的结构、生化和生物物理特征以及它们最近的结构-功能分析。我们还重点介绍了未来针对NEET蛋白的研究途径，并提出了NEETs在健康和疾病中的重要作用。本文是名为：铁硫蛋白：分析、结构、功能、生物合成和疾病的特刊的一部分。
