Nicotinamide Adenine Dinucleotide-induced Multimerization of the Co-repressor CtBP1 Relies on a Switching Tryptophan

Madison, Dana L.; Wirz, J; Siess, Don C.; Lundblad, James R.

doi:10.1074/jbc.m113.493569

Cited by 35 publications

(71 citation statements)

References 36 publications

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“…This is contrary to a previous report demonstrating that CtBP2 mutants lacking dehydogenase activity display corresponding decreases in corepressor activity (20). These opposing observations could be reconciled by findings in a recent study suggesting that some catalytic mutants of CtBP also display reduced binding affinity for NADH, although these mutants are still capable of forming CtBP dimers (63). Furthermore, a study by Madison et al (63) recently proposed that CtBPs not only form functional dimers, but also higher-order tetramers that are also essential to CtBP function and are controlled by a tryptophan residue (Trp318) that acts as dimerization switch following binding to NADH.…”

Section: Metabolic and Redox Sensitivity Of Ctbpscontrasting

confidence: 80%

“…Although both forms of this dinucleotide are capable of inducing CtBP dimerization, CtBPs bind NADH with up to 100-fold higher affinity than NAD+, suggesting that these proteins are in fact sensitive to the ratio of NADH to NAD+ within the nucleus (18,61,62). Nonetheless, additional reports have suggested that CtBPs bind both NAD+ and NADH with similar affinity (17,63). Therefore, further investigation is required to determine which binding paradigm is correct.…”

Section: Metabolic and Redox Sensitivity Of Ctbpsmentioning

confidence: 99%

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C-terminal binding proteins: central players in development and disease

Stankiewicz¹,

Gray²,

Winter

et al. 2014

Biomolecular Concepts

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C-terminal binding proteins (CtBPs) were initially identified as binding partners for the E1A-transforming proteins. Although the invertebrate genome encodes one CtBP protein, two CtBPs (CtBP1 and CtBP2) are encoded by the vertebrate genome and perform both unique and duplicative functions. CtBP1 and CtBP2 are closely related and act as transcriptional corepressors when activated by nicotinamide adenine dinucleotide binding to their dehydrogenase domains. CtBPs exert transcriptional repression primarily via recruitment of a corepressor complex to DNA that consists of histone deacetylases (HDACs) and histone methyltransferases, although CtBPs can also repress transcription through HDAC-independent mechanisms. More recent studies have demonstrated a critical function for CtBPs in the transcriptional repression of pro-apoptotic genes such as Bax, Puma, Bik, and Noxa. Nonetheless, although recent efforts have characterized the essential involvement of CtBPs in promoting cellular survival, the dysregulation of CtBPs in both neurodegenerative disease and cancers remains to be fully elucidated.

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Section: Metabolic and Redox Sensitivity Of Ctbpscontrasting

confidence: 80%

Section: Metabolic and Redox Sensitivity Of Ctbpsmentioning

confidence: 99%

C-terminal binding proteins: central players in development and disease

Stankiewicz¹,

Gray²,

Winter

et al. 2014

Biomolecular Concepts

View full text Add to dashboard Cite

show abstract

“…Our initial experiments were carried out using the minimal dehydrogenase domain constructs that we had previously used for crystallization, CtBP1 (28 -353) and CtBP2 (37). In contrast with a previous report (30), our SEC-MALS experiments on CtBP lacking the full C terminus showed molecular weights considerably larger than dimers in the presence of sufficient NADH (Fig. 1A).…”

Section: Mals Shows That Both Ctbp1 and Ctbp2 Assemble Into Tetramerscontrasting

confidence: 58%

Assembly of human C-terminal binding protein (CtBP) into tetramers

Bellesis

Jecrois

Hayes

et al. 2018

Journal of Biological Chemistry

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C-terminal binding protein 1 (CtBP1) and CtBP2 are transcriptional coregulators that repress numerous cellular processes, such as apoptosis, by binding transcription factors and recruiting chromatin-remodeling enzymes to gene promoters. The NAD(H)-linked oligomerization of human CtBP is coupled to its co-transcriptional activity, which is implicated in cancer progression. However, the biologically relevant level of CtBP assembly has not been firmly established; nor has the stereochemical arrangement of the subunits above that of a dimer. Here, multi-angle light scattering (MALS) data established the NAD- and NADH-dependent assembly of CtBP1 and CtBP2 into tetramers. An examination of subunit interactions within CtBP1 and CtBP2 crystal lattices revealed that both share a very similar tetrameric arrangement resulting from assembly of two dimeric pairs, with specific interactions probably being sensitive to NAD(H) binding. Creating a series of mutants of both CtBP1 and CtBP2, we tested the hypothesis that the crystallographically observed interdimer pairing stabilizes the solution tetramer. MALS data confirmed that these mutants disrupt both CtBP1 and CtBP2 tetramers, with the dimer generally remaining intact, providing the first stereochemical models for tetrameric assemblies of CtBP1 and CtBP2. The crystal structure of a subtle destabilizing mutant suggested that small structural perturbations of the hinge region linking the substrate- and NAD-binding domains are sufficient to weaken the CtBP1 tetramer. These results strongly suggest that the tetramer is important in CtBP function, and the series of CtBP mutants reported here can be used to investigate the physiological role of the tetramer.

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“…2). This Trp has recently been implicated both as a dimerization switch in CtBP1[38] and in models of the binding of the brefeldin A (BFA) moiety in the BFA-ADP ribosyl conjugate of rat CtBP1/BARS[39]. Interestingly, the MTOB S8 atom centers over the CtBP Trp318/324 indole, rather than orienting its lone pair of electrons towards the positively charged CtBP Arg97/103, suggesting a sulfur-π interaction [40,41].…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design

et al. 2014

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The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory D-isomer specific 2-hydroxyacid dehydrogenase (D2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD+ revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that links MTOB with an NAD+ phosphate. Neither feature is present in other D2-HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti-neoplastic CtBP inhibitors.

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Nicotinamide Adenine Dinucleotide-induced Multimerization of the Co-repressor CtBP1 Relies on a Switching Tryptophan

Cited by 35 publications

References 36 publications

C-terminal binding proteins: central players in development and disease

C-terminal binding proteins: central players in development and disease

Assembly of human C-terminal binding protein (CtBP) into tetramers

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design

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