Activity and structure of human (d)CTP deaminase CDADC1

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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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-05-05
DOI
https://doi.org/10.1073/pnas.2424245122
Citations
1
Primary Topic
Biochemical and Molecular Research
Type
article
Field-Weighted Citation Impact
0.81

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article

Activity and structure of human (d)CTP deaminase CDADC1

Olga Gewartowska, Tapan Kanai, Alexander Wlodawer, Renbin Yang et al.
1 citations
Proceedings of the National Academy of Sciences
Biochemical and Molecular Research
0.81
article

Activity and structure of human (d)CTP deaminase CDADC1

Olga Gewartowska, Tapan Kanai, Alexander Wlodawer, Renbin Yang, Ishan Rathore, Mariusz Czarnocki‐Cieciura, Anton Slyvka, G.T. Lountos, Matthias Bochtler, Krzysztof Skowronek
article en
1 citations

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.

Proceedings of the National Academy of SciencesVol. 122(19)
Leidos (United States) (US), International Institute of Molecular and Cell Biology (PL), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (MY), Leidos Biomedical Research Inc. (United States)
Frederick National Laboratory for Cancer Research, Fundacja na rzecz Nauki Polskiej, Narodowe Centrum Nauki, Uniwersytet Warszawski, Międzynarodowy Instytut Biologii Molekularnej i Komórkowej w Warszawie, Narodowa Agencja Wymiany Akademickiej, National Institutes of Health, HORIZON EUROPE Framework Programme, National Cancer Institute
Openalex Percentile: Top 28%
Biochemical and Molecular Research
0.81
DOIOpen Access PDFOpenAlex
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