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Crystal structure and functional implications of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases

Author

Listed:
  • Chia-Shin Yang

    (Genomics BioSci & Tech Co. Ltd.)

  • Tzu-Ping Ko

    (Institute of Biological Chemistry, Academia Sinica)

  • Chao-Jung Chen

    (China Medical University
    China Medical University Hospital)

  • Mei-Hui Hou

    (Genomics BioSci & Tech Co. Ltd.)

  • Yu-Chuan Wang

    (Trade Wind Biotech Co. Ltd.)

  • Yeh Chen

    (National Chung Hsing University)

Abstract

Purine-containing nucleotide second messengers regulate diverse cellular activities. Cyclic di-pyrimidines mediate anti-phage functions in bacteria; however, the synthesis mechanism remains elusive. Here, we determine the high-resolution structures of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases (CD-NTases) in clade E (CdnE) in its apo, substrate-, and intermediate-bound states. A conserved (R/Q)xW motif controlling the pyrimidine specificity of donor nucleotide is identified. Mutation of Trp or Arg from the (R/Q)xW motif to Ala rewires its specificity to purine nucleotides, producing mixed purine-pyrimidine cyclic dinucleotides (CDNs). Preferential binding of uracil over cytosine bases explains the product specificity of cyclic di-pyrimidine-synthesizing CdnE to cyclic di-UMP (cUU). Based on the intermediate-bound structures, a synthetic pathway for cUU containing a unique 2’3’-phosphodiester linkage through intermediate pppU[3’−5’]pU is deduced. Our results provide a framework for pyrimidine selection and establish the importance of conserved residues at the C-terminal loop for the specificity determination of CD-NTases.

Suggested Citation

  • Chia-Shin Yang & Tzu-Ping Ko & Chao-Jung Chen & Mei-Hui Hou & Yu-Chuan Wang & Yeh Chen, 2023. "Crystal structure and functional implications of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40787-9
    DOI: 10.1038/s41467-023-40787-9
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    References listed on IDEAS

    as
    1. Tzu-Ping Ko & Yu-Chuan Wang & Chia-Shin Yang & Mei-Hui Hou & Chao-Jung Chen & Yi-Fang Chiu & Yeh Chen, 2022. "Crystal structure and functional implication of bacterial STING," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Aaron T. Whiteley & James B. Eaglesham & Carina C. de Oliveira Mann & Benjamin R. Morehouse & Brianna Lowey & Eric A. Nieminen & Olga Danilchanka & David S. King & Amy S. Y. Lee & John J. Mekalanos & , 2019. "Bacterial cGAS-like enzymes synthesize diverse nucleotide signals," Nature, Nature, vol. 567(7747), pages 194-199, March.
    3. Shirin Fatma & Arpita Chakravarti & Xuankun Zeng & Raven H. Huang, 2021. "Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    4. Samuel J. Hobbs & Tanita Wein & Allen Lu & Benjamin R. Morehouse & Julia Schnabel & Azita Leavitt & Erez Yirmiya & Rotem Sorek & Philip J. Kranzusch, 2022. "Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity," Nature, Nature, vol. 605(7910), pages 522-526, May.
    5. Thomas A. Steitz, 1998. "A mechanism for all polymerases," Nature, Nature, vol. 391(6664), pages 231-232, January.
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    7. Daniel Cohen & Sarah Melamed & Adi Millman & Gabriela Shulman & Yaara Oppenheimer-Shaanan & Assaf Kacen & Shany Doron & Gil Amitai & Rotem Sorek, 2019. "Cyclic GMP–AMP signalling protects bacteria against viral infection," Nature, Nature, vol. 574(7780), pages 691-695, October.
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