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THE 1.55A CRYSTAL STRUCTURE of NAF1 (MINER1): THE REDOX-ACTIVE 2FE-2S PROTEIN
Structural highlights
DiseaseCISD2_HUMAN Defects in CISD2 are the cause of Wolfram syndrome type 2 (WFS2) [MIM:604928. A rare disorder characterized by juvenile-onset insulin-dependent diabetes mellitus with optic atrophy. Other manifestations include diabetes insipidus, sensorineural deafness, dementia, psychiatric illnesses. WFS2 patients additionally show a strong bleeding tendency and gastrointestinal ulceration. Diabetes insipidus may be absent.[1] FunctionCISD2_HUMAN Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum. Participates in the interaction of BCL2 with BECN1 and is required for BCL2-mediated depression of endoplasmic reticulum Ca(2+) stores during autophagy. Contributes to BIK-initiated autophagy, while it is not involved in BIK-dependent activation of caspases. Involved in life span control, probably via its function as regulator of autophagy.[2] [3] Publication Abstract from PubMedNAF-1 is an important [2Fe-2S] NEET protein associated with human health and disease. A mis-splicing mutation in NAF-1 results in Wolfram Syndrome type 2, a lethal childhood disease. Upregulation of NAF-1 is found in epithelial breast cancer cells, and suppression of NAF-1 expression by knockdown significantly suppresses tumor growth. Key to NAF-1 function is the NEET fold with its [2Fe-2S] cluster. In this work, the high-resolution structure of native NAF-1 was determined to 1.65 A resolution (R factor = 13.5%) together with that of a mutant in which the single His ligand of its [2Fe-2S] cluster, His114, was replaced by Cys. The NAF-1 H114C mutant structure was determined to 1.58 A resolution (R factor = 16.0%). All structural differences were localized to the cluster binding site. Compared with native NAF-1, the [2Fe-2S] clusters of the H114C mutant were found to (i) be 25-fold more stable, (ii) have a redox potential that is 300 mV more negative and (iii) have their cluster donation/transfer function abolished. Because no global structural differences were found between the mutant and the native (wild-type) NAF-1 proteins, yet significant functional differences exist between them, the NAF-1 H114C mutant is an excellent tool to decipher the underlying biological importance of the [2Fe-2S] cluster of NAF-1 in vivo. A point mutation in the [2Fe-2S] cluster binding region of the NAF-1 protein (H114C) dramatically hinders the cluster donor properties.,Tamir S, Eisenberg-Domovich Y, Conlan AR, Stofleth JT, Lipper CH, Paddock ML, Mittler R, Jennings PA, Livnah O, Nechushtai R Acta Crystallogr D Biol Crystallogr. 2014 Jun;70(Pt 6):1572-8. doi:, 10.1107/S1399004714005458. Epub 2014 May 23. PMID:24914968[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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