Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/14413
Title: Elucidation of novel functional and regulatory characteristics of the mammalian transcriptional co-repressor CtBP2
Authors: THIO SWEE CHIN, SHARON
Keywords: C-terminal binding protein, CtBP, transcription intermediary factor, TIF1a, KRIP-1, transcriptional co-repressor
Issue Date: 3-Jan-2005
Source: THIO SWEE CHIN, SHARON (2005-01-03). Elucidation of novel functional and regulatory characteristics of the mammalian transcriptional co-repressor CtBP2. ScholarBank@NUS Repository.
Abstract: The C-terminal Binding Protein 2 (CtBP2) was recently demonstrated that CtBP is a dimeric NAD+-regulated D-isomer specific 2-hydroxy acid dehydrogenase. We demonstrate that amino acid substitutions at Gly189 in the conserved NAD+ binding fold abrogates CtBP2 homodimerization and co-repressor activity. Mutations at Arg272 (substrate-binding domain) and at His321 (catalytic domain) also result in loss of CtBP2 co-repressor activity. High resolution serial C-terminal deletion analysis revealed a novel N-terminal repression domain that is distinct from its dehydrogenase domain. Our results suggest that CtBP2 co-repressor function is regulated, at least in part, through the effect of NADH on CtBP2 homodimerization. We have identified CtBP2 as a co-repressor of TIF1a and KRIP-1, members of the TIF1 family of transcriptional repressors. CtBP2 makes a direct functional interaction with TIF1a via a conserved PMDLS CtBP binding site in the TIF1a PHD-bromodomain. A weaker interaction between CtBP2 and the KRIP-1 is associated with the less conserved TLDLT sequence in the KRIP-1 PHD-bromodomain. Site-directed mutagenesis of DL to AS in the PMDLS sequence of the isolated TIF1a PHD-bromodomain abrogates binding to and co-localization with CtBP, and results in loss of transcriptional repression ability of the TIF1a PHD-bromodomain. We identified a novel interaction between CtBP2 and the RBCC domain of TIF1a and KRIP-1. We propose that the formation of repressor complexes between CtBP2 and TIF1a/KRIP-1 is mediated by a novel interaction with the RBCC domain, in addition to the conserved PMDLS CtBP binding motif.
URI: http://scholarbank.nus.edu.sg/handle/10635/14413
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acknowledgements.pdf27.37 kBAdobe PDF

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contents.pdf67.36 kBAdobe PDF

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list of figures.pdf140.15 kBAdobe PDF

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Abstract for thesis.pdf24.34 kBAdobe PDF

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1 Introduction.pdf660.79 kBAdobe PDF

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2 Materials and Methods.pdf236.68 kBAdobe PDF

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3 Results CtBP and 2HAD.pdf1.05 MBAdobe PDF

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4 Results CtBP and TIF1.pdf1.11 MBAdobe PDF

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5 Conclusions.pdf25.97 kBAdobe PDF

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6 References.pdf98.96 kBAdobe PDF

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