Oligomeric form of C‐terminal‐binding protein coactivates NeuroD1‐mediated transcription

Ray, Subir K.; Li, Hui J.; Leiter, Andrew B.

doi:10.1002/1873-3468.12501

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…Previous investigations into the role of assembly in CtBP have investigated the activity of mutants specifically designed to disrupt the CtBP dimer (33)(34)(35)(36). Our results strongly suggest that the CtBP dimer is required for the assembly of a CtBP tetramer formed from the pairing of two CtBP dimers.…”

Section: Assembly Of Tetrameric Ctbpmentioning

confidence: 51%

“…Regulation of gene expression through the oligomerization of transcriptional factors is an important paradigm (27,28). In the case of CtBP, substantial evidence exists that oligomerization is linked with NAD(H) binding (3, 25, 29 -32), and dimerdestabilizing mutants have been found to inhibit transcriptional function (33)(34)(35)(36). Assembly of CtBP has primarily been considered in terms of dimers, as NADH-bound CtBP crystal structures reveal a predominant dimer with extensive interactions between subunit pairs (23,37,38).…”

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confidence: 99%

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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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Section: Assembly Of Tetrameric Ctbpmentioning

confidence: 51%

mentioning

confidence: 99%

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

Bellesis

Jecrois

Hayes

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

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“…CtBP binding to NAD(H) is necessary for its normal functions, and substantial evidence indicates that NAD(H) binding supports CtBP dimerization and tetramerization ( Kumar et al 2002 ; Balasubramanian et al 2003 ; Sutrias-Grau & Arnosti 2004 ; Mani-Telang and Arnosti 2007 ; Madison et al 2013 ; Bellesis et al 2018 ; Jecrois et al 2021 ). Tetramerization has been shown to be required for transcriptional repression, as tetramer-destabilizing mutants have compromised transcriptional regulatory activity ( Bhambhani et al 2011 ; Ray et al 2017 ; Bi et al 2018 ; Jecrois et al 2021 ). Additionally, it is the oligomeric form of CtBP that associates with other factors, suggesting this is the relevant form for transcriptional regulation ( Shi et al 2003 ; Jecrois et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Cynosure of CtBP: Evolution of a Bilaterian Transcriptional Corepressor

Raicu

Kadiyala

Niblock

et al. 2023

Molecular Biology and Evolution

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Evolution of sequence-specific transcription factors clearly drives lineage-specific innovations, but less is known about how changes in the central transcriptional machinery may contribute to evolutionary transformations. In particular, transcriptional regulators are rich in intrinsically disordered regions that appear to be magnets for evolutionary innovation. The C-terminal Binding Protein (CtBP) is a transcriptional corepressor derived from an ancestral lineage of alpha hydroxyacid dehydrogenases; it is found in mammals and invertebrates, and features a core NAD-binding domain as well as an unstructured C-terminus (CTD) of unknown function. CtBP can act on promoters and enhancers to repress transcription through chromatin-linked mechanisms. Our comparative phylogenetic study shows that CtBP is a bilaterian innovation whose CTD of about 100 residues is present in almost all orthologs. CtBP CTDs contain conserved blocks of residues and retain a predicted disordered property, despite having variations in the primary sequence. Interestingly, the structure of the C-terminus has undergone radical transformation independently in certain lineages including flatworms and nematodes. Also contributing to CTD diversity is the production of myriad alternative RNA splicing products, including the production of “short” tailless forms of CtBP in Drosophila. Additional diversity stems from multiple gene duplications in vertebrates, where up to five CtBP orthologs have been observed. Vertebrate lineages show fewer major modifications in the unstructured CTD, possibly because gene regulatory constraints of the vertebrate body plan place specific constraints on this domain. Our study highlights the rich regulatory potential of this previously unstudied domain of a central transcriptional regulator.

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“…CtBP binding to NAD(H) is necessary for its normal functions, and substantial evidence indicates that NAD(H) binding supports CtBP dimerization and tetramerization (Kumar et al 2002;Balasubramanian et al 2003;Sutrias-Grau & Arnosti 2004;Mani-Telang et al 2007;Madison et al 2013;Bellesis et al 2018;Jecrois et al 2021). Tetramerization has been shown to be required for transcriptional repression, as tetramer-destabilizing mutants have compromised transcriptional regulatory activity (Bhambhani et al 2011;Bi et al 2018;Ray et al 2017;Jecrois et al 2021). Additionally, it is the oligomeric form of CtBP that associates with other factors, suggesting this is the relevant form for transcriptional regulation (Shi et al 2003;Jecrois et al 2021).…”

Section: Introductionmentioning

confidence: 99%

The cynosure of CtBP: evolution of a bilaterian transcriptional corepressor

Raicu

Kadiyala

Niblock

et al. 2022

Preprint

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Evolution of sequence-specific transcription factors clearly drives lineage-specific innovations, but less is known about how changes in the central transcriptional machinery may contribute to evolutionary transformations. In particular, transcriptional regulators are rich in intrinsically disordered regions that appear to be magnets for evolutionary innovation. The C-terminal Binding Protein (CtBP) is a transcriptional corepressor derived from an ancestral lineage of alpha hydroxyacid dehydrogenases; it is found in mammals and invertebrates, and features a core NAD-binding domain as well as an unstructured C-terminus (CTD) of unknown function. CtBP can act on promoters and enhancers to repress transcription through chromatin-linked mechanisms. Our comparative phylogenetic study shows that CtBP is a bilaterian innovation whose CTD of about 100 residues is present in almost all orthologs. CtBP CTDs contain conserved blocks of residues and retain a predicted disordered property, despite having variations in the primary sequence. Interestingly, the structure of the C-terminus has undergone radical transformation independently in certain lineages including flatworms and nematodes. Also contributing to CTD diversity is the production of myriad alternative RNA splicing products, including the production of short tailless forms of CtBP in Drosophila. Additional diversity stems from multiple gene duplications in vertebrates, where up to five CtBP orthologs have been observed. Vertebrate lineages show fewer major modifications in the unstructured CTD, possibly because gene regulatory constraints of the vertebrate body plan place specific constraints on this domain. Our study highlights the rich regulatory potential of this previously unstudied domain of a central transcriptional regulator.

show abstract

Oligomeric form of C‐terminal‐binding protein coactivates NeuroD1‐mediated transcription

Cited by 7 publications

References 29 publications

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

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

The Cynosure of CtBP: Evolution of a Bilaterian Transcriptional Corepressor

The cynosure of CtBP: evolution of a bilaterian transcriptional corepressor

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