Karmi, OlaMarjault, Henri-BaptistePesce, LucaCarloni, PaoloOnuchic, José N.Jennings, Patricia A.Mittler, RonNechushtai, Rachel2018-07-112018-07-112018Karmi, Ola, Marjault, Henri-Baptiste, Pesce, Luca, et al.. "The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease." <i>Journal of Biological Inorganic Chemistry,</i> 23, no. 4 (2018) Springer: 599-612. https://doi.org/10.1007/s00775-018-1538-8.https://hdl.handle.net/1911/102395NEET proteins comprise a new class of [2Fe-2S] cluster proteins. In human, three genes encode for NEET proteins: cisd1 encodes mitoNEET (mNT), cisd2 encodes the Nutrient-deprivation autophagy factor-1 (NAF-1) and cisd3 encodes MiNT (Miner2). These recently discovered proteins play key roles in many processes related to normal metabolism and disease. Indeed, NEET proteins are involved in iron, Fe-S, and reactive oxygen homeostasis in cells and play an important role in regulating apoptosis and autophagy. mNT and NAF-1 are homodimeric and reside on the outer mitochondrial membrane. NAF-1 also resides in the membranes of the ER associated mitochondrial membranes (MAM) and the ER. MiNT is a monomer with distinct asymmetry in the molecular surfaces surrounding the clusters. Unlike its paralogs mNT and NAF-1, it resides within the mitochondria. NAF-1 and mNT share similar backbone folds to the plant homodimeric NEET protein (At-NEET), while MiNT's backbone fold resembles a bacterial MiNT protein. Despite the variation of amino acid composition among these proteins, all NEET proteins retained their unique CDGSH domain harboring their unique 3Cys:1His [2Fe-2S] cluster coordination through evolution. The coordinating exposed His was shown to convey the lability to the NEET proteins' [2Fe-2S] clusters. In this minireview, we discuss the NEET fold and its structural elements. Special attention is given to the unique lability of the NEETs' [2Fe-2S] cluster and the implication of the latter to the NEET proteins' cellular and systemic function in health and disease.engThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Journal articleCisd(1–3) encoded NEET proteinsIron-sulfur clustersNEET-cluster labilityNEET-fold[2Fe-2S]https://doi.org/10.1007/s00775-018-1538-8