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Activity and structure of human (d)CTP deaminase CDADC1

  1. Author:
    Slyvka, Anton [ORCID]
    Rathore, Ishan
    Yang, Renbin
    Gewartowska, Olga
    Kanai, Tapan
    Lountos,George [ORCID]
    Skowronek, Krzysztof [ORCID]
    Czarnocki-Cieciura, Mariusz [ORCID]
    Wlodawer,Alexander [ORCID]
    Bochtler, Matthias [ORCID]

  2. Author Address

    Laboratory of Structural Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw 02-109, Poland., Center for Structural Biology, National Cancer Institute, NIH, Frederick, MD 21702., Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick, MD 21701., Genome Engineering Facility, International Institute of Molecular and Cell Biology in Warsaw, Warsaw 02-109, Poland., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Biophysics Facility, International Institute of Molecular and Cell Biology in Warsaw, Warsaw 02-109, Poland., Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, Warsaw 02-109, Poland., Institute of Biochemistry and Biophysics, Warsaw 02-106, Poland.,
    1. Year: 2025
    2. Date: May 13
    3. Epub Date: 2025 05 05
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 122
    2. 19
    3. Pages: e2424245122
  4. Type of Article: Article
  5. Article Number: e2424245122
  1. Abstract:

    Vertebrates have evolved an understudied protein termed CDADC1 (NYD-SP15) that contains an inactive N-terminal and active C-terminal DCTD-like domain. Here, we show that human CDADC1 is a (d)CTP-specific deaminase, with a roughly 2-fold in vitro preference for dCTP over CTP. We determined high-resolution cryo-EM structures of CDADC1 in the absence of substrate and in complex with dCTP and 5-methyl-dCTP. The structures show that CDADC1 forms trimers and dimers of trimers in solution. The (d)CTP substrate is selected by a narrow pocket for the cytosine base and multiple lysine and arginine contacts to the triphosphate. Substrate binding promotes the association of trimers into hexamers and the transition of the hexamers from a loose to a tighter arrangement. Genetic experiments in mice show that loss of Cdadc1 is surprisingly well tolerated, even in the absence of the dCMP deaminase Dctd that is considered as the main source of dUMP, the precursor of dTTP.

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External Sources

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  2. DOI: 10.1073/pnas.2424245122
  3. PMID: 40324085

Library Notes

  1. Fiscal Year: FY2024-2025
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