Transcription Corepressor CtBP Is an NAD+-Regulated Dehydrogenase

Department of Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Molecular Cell (Impact Factor: 14.02). 11/2002; 10(4):857-69. DOI: 10.1016/S1097-2765(02)00650-0
Source: PubMed


Transcriptional repression is based on the selective actions of recruited corepressor complexes, including those with enzymatic activities. One well-characterized developmentally important corepressor is the C-terminal binding protein (CtBP). Although intriguingly related in sequence to D2 hydroxyacid dehydrogenases, the mechanism by which CtBP functions remains unclear. We report here biochemical and crystallographic studies which reveal that CtBP is a functional dehydrogenase. In addition, both a cofactor-dependent conformational change, with NAD(+) and NADH being equivalently effective, and the active site residues are linked to the binding of the PXDLS consensus recognition motif on repressors, such as E1A and RIP140. Together, our data suggest that CtBP is an NAD(+)-regulated component of critical complexes for specific repression events in cells.

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    • "Astrocyte calcium signals are regulated by NAD+/NADH redox state (Requardt et al., 2012; Wilhelm and Hirrlinger, 2012), and changes in intracellular NAD+ and NADH levels arising from lactate fluxes may affect their binding to transcription factors and influence gene expression (Nakamura et al., 2012). For example, the transcription co-repressor, C-terminal binding protein (CtBP), is a dehydrogenase that undergoes conformational change with binding of NAD+ and NADH; NADH has a much higher affinity for CtBP, allowing it to serve as a redox sensor that destabilizes interactions with CtBP and transcription factors (Kumar et al., 2002; Fjeld et al., 2003). Increased NADH levels are thought to underlie seizure-induced increased expression of brain-derived neurotrophic factor (BDNF) and its receptor TrkB (Garriga-Canut et al., 2006). "
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    • "Journal of Biomedicine and Biotechnology on NADH levels, and in particular high NADH levels promote CtBP dimerization as well as its interaction with other transcriptional repressors such as HIC1 [44] [45] [46] [47]. Cellular redox changes sensed by CtBP alter the affinity of the CtBP for HIC1 leading to a reduction of CtBP recruitment to Sirt1 promoter and hence derepression of its gene expression [43]. "
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