CtBP/BARS: a dual-function protein involved in transcription co-repression and Golgi membrane fission

Abstract

C‐terminal‐binding protein/brefeldin A‐ADP ribosylated substrate (CtBP/BARS) plays key roles in development and oncogenesis as a transcription co‐repressor, and in intracellular traffic as a promoter of Golgi membrane fission. Co‐repressor activity is regulated by NAD(H) binding to CtBP/BARS, while membrane fission is associated with its acyl‐CoA‐dependent acyltransferase activity. Here, we report the crystal structures of rat CtBP/BARS in a binary complex with NAD(H), and in a ternary complex with a PIDLSKK peptide mimicking the consensus motif (PXDLS) recognized in CtBP/BARS cellular partners. The structural data show CtBP/BARS in a NAD(H)‐bound dimeric form; the peptide binding maps the recognition site for DNA‐binding proteins and histone deacetylases to an N‐terminal region of the protein. The crystal structure together with the site‐directed mutagenesis data and binding experiments suggest a rationale for the molecular mechanisms underlying the two fundamental co‐existing, but diverse, activities supported by CtBP/BARS in the nucleus and in Golgi membranes.

RETRACTED: Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex

“…12). In contrast to Sir2, CtBP is affected by both NAD ϩ and NADH (11,13,14). Although free NAD ϩ (presumably the relevant fraction for Sir2 regulation) cannot be measured directly, the ratio of cytoplasmic free NAD ϩ :NADH can be derived from the lactate and pyruvate concentrations (15).…”

CtBPs promote mitotic fidelity through their activities in the cell nucleus

“…Structural and mutational analysis of CtBPs have identified discreet functional domains within the proteins; the N terminus forms a hydrophobic cleft that contacts the PxDLS motif in many of its partner transcriptional regulators, and the core central domain undergoes NAD þ /NADH-dependent dimerization, which is required for the assembly of the chromatinmodifying complex (Nardini et al, 2003;Quinlan et al, 2006;Chinnadurai, 2007;Kuppuswamy et al, 2008). CtBP chromatin-modifying complexes are readily detectable in proliferating cancer cells in culture (Shi et al, 2003), and there is evidence that their formation is increased under conditions of increased glycolysis, for example, in response to hypoxia (Zhang et al, 2002).…”

“…To test this assumption, we generated GST-CtBP DN V72R. V72 in CtBP2 is a critical residue in the PxDLS-binding domain, and its mutation to arginine (or mutation of the equivalent residue in CtBP1) has been clearly demonstrated by independent research groups to abrogate binding to PxDLS-containing proteins, including both chromatin-modifying enzymes and DNA-binding transcription factors (Nardini et al, 2003;Quinlan et al, 2006;Kuppuswamy et al, 2008). Thus, this mutant of CtBP DN would be unable to effectively compete with CtBPs for binding to PxDLS-motif-containing proteins.…”

Functional Anthology of Intrinsic Disorder. 2. Cellular Components, Domains, Technical Terms, Developmental Processes, and Coding Sequence Diversities Correlated with Long Disordered Regions

“…70 CtBP is a moonlighting protein that fulfills different functions in the cell depending on cellular localization. 71 In isolated Golgi apparatus the CtBP3 isoform (previously known as BARS, Brefeldin A-ADP Ribosylated Substrate, and recently renamed as short-CtBP1 or CtBP1-S) has been shown to be a key component of the machinery controlling Golgi tubule fission.…”