The C-terminal binding protein (CtBP) is an evolutionarily conserved transcriptional corepressor found in multicellular eukaryotes. Multiple forms of the protein are typically found in animal cells, produced from separate genes and by alternative splicing. CtBP isoforms have also been implicated in cytoplasmic functions, including Golgi fission and vesicular trafficking. All forms of CtBP contain a conserved core domain that is homologous to α-hydroxyacid dehydrogenases, and a subset of isoforms (CtBP L ) contain extensions at the C-terminus. Despite distinct developmental profiles and knockout phenotypes in the mouse, the properties of different isoforms of the protein are found to be similar in many transcriptional assays. We have investigated the expression and conservation of distinct isoforms of the CtBP protein in insects, and find that the expression of multiple, developmentally regulated isoforms is widely conserved. In a variety of Drosophila species, the relative abundance of CtBP L to CtBP S drops sharply after embryogenesis, revealing a conserved developmental shift. Despite the overall lower levels of this isoform, bioinformatic analysis reveals that exons encoding the C-terminal extension in CtBP L are conserved from Diptera to Coleoptera, suggesting that the CtBP L isoform contributes an important, evolutionarily conserved function.
CtBP corepressor proteins potentiate the activity of many metazoan transcriptional repressors. These proteins are homologous to prokaryotic D-2-hydroxyacid dehydrogenases, possessing an NAD/NADH binding fold and conserved active site residues. When expressed in Drosophila, a catalytic site mutant retains biological activity, however, we find that an NAD binding mutant lacks biological activity. The NAD mutant, similar to a dimerization mutant, is expressed at low levels, indicating that binding of NAD/NADH may affect CtBP stability. These data support the idea that the ancestral dehydrogenase activity is not required for CtBP function, and NAD binding may play a regulatory, rather than catalytic, role.
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