7p0p | pdb_00007p0p
NAF-1 bound to M1 molecule
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 PubMedElevated levels of mitochondrial iron and reactive oxygen species (ROS) accompany the progression of diabetes, negatively impacting insulin production and secretion from pancreatic cells. In search for a tool to reduce mitochondrial iron and ROS levels, we arrived at a molecule that destabilizes the [2Fe-2S] clusters of NEET proteins (M1). Treatment of db/db diabetic mice with M1 improved hyperglycemia, without the weight gain observed with alternative treatments such as rosiglitazone. The molecular interactions of M1 with the NEET proteins mNT and NAF-1 were determined by X-crystallography. The possibility of controlling diabetes by molecules that destabilize the [2Fe-2S] clusters of NEET proteins, thereby reducing iron-mediated oxidative stress, opens a new route for managing metabolic aberration such as in diabetes. An anti-diabetic drug targets NEET (CISD) proteins through destabilization of their [2Fe-2S] clusters.,Marjault HB, Karmi O, Zuo K, Michaeli D, Eisenberg-Domovich Y, Rossetti G, de Chassey B, Vonderscher J, Cabantchik I, Carloni P, Mittler R, Livnah O, Meldrum E, Nechushtai R Commun Biol. 2022 May 10;5(1):437. doi: 10.1038/s42003-022-03393-x. PMID:35538231[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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