Department of Biochemistry and Molecular Pharmacology; Schiffer Lab; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry | Biological Phenomena, Cell Phenomena, and Immunity | Cells | Cellular and Molecular Physiology | Structural Biology
C-terminal binding proteins 1 and 2 (CtBP1 and CtBP2) are transcriptional regulators that activate or repress many genes involved in cellular development, apoptosis and metastasis. CtBP proteins are activated under hypoxic conditions where NAD(H) levels tend to be higher. NADH-dependent activation of CtBP2 has direct implication in multiple types of cancers and poor patient prognosis. Previous studies have proposed dimeric CtBP as the relevant oligomeric state, however our studies with multi-angle light scattering have shown that the primary effect of NADH binding is to promote the assembly of two CtBP dimers into tetramers. Here, we present the cryoEM structures of two different constructs of CtBP2 corroborating that the native state of CtBP2 in the presence of NADH is indeed tetrameric. The physiological relevance of tetrameric CtBP2 was tested in HCT116; CtBP2 -/- cells transfected with tetramer destabilizing mutants. Mutants that inhibit tetramer formation show a decrease in expression of the CtBP transcriptional target TIAM1 and exhibit a decrease in the ability to promote cell migration. Together with our cryoEM studies, these results highlight the tetramer as the functional oligomeric form of CtBP2.
biochemistry, C-terminal binding proteins 1 and 2, transcriptional regulators, genes, cancers, tetramers
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DOI of Published Version
bioRxiv 2020.04.06.027573; doi: https://doi.org/10.1101/2020.04.06.027573. Link to preprint on bioRxiv service.
Now published in Structure, doi:https://doi.org/10.1016/j.str.2020.11.008.
Jecrois AM, Dcona MM, Deng X, Bandyopadhyay D, Grossman SR, Schiffer CA, Royer WE. (2020). CryoEM Structure of CtBP2 Confirms Tetrameric Architecture [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.04.06.027573. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1672
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