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Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity

Author

Listed:
  • Takahide Kouno

    (University of Massachusetts Medical School)

  • Tania V. Silvas

    (University of Massachusetts Medical School)

  • Brendan J. Hilbert

    (University of Massachusetts Medical School)

  • Shivender M. D. Shandilya

    (University of Massachusetts Medical School)

  • Markus F. Bohn

    (University of Massachusetts Medical School
    Present address: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, USA)

  • Brian A. Kelch

    (University of Massachusetts Medical School)

  • William E. Royer

    (University of Massachusetts Medical School)

  • Mohan Somasundaran

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Nese Kurt Yilmaz

    (University of Massachusetts Medical School)

  • Hiroshi Matsuo

    (Basic Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory
    Molecular Biology and Biophysics, Institute for Molecular Virology, University of Minnesota)

  • Celia A. Schiffer

    (University of Massachusetts Medical School)

Abstract

Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 Å. This structure not only visualizes the active site poised for catalysis of APOBEC3A, but pinpoints the residues that confer specificity towards CC/TC motifs. The APOBEC3A–ssDNA complex defines the 5′–3′ directionality and subtle conformational changes that clench the ssDNA within the binding groove, revealing the architecture and mechanism of ssDNA recognition that is likely conserved among all polynucleotide deaminases, thereby opening the door for the design of mechanistic-based therapeutics.

Suggested Citation

  • Takahide Kouno & Tania V. Silvas & Brendan J. Hilbert & Shivender M. D. Shandilya & Markus F. Bohn & Brian A. Kelch & William E. Royer & Mohan Somasundaran & Nese Kurt Yilmaz & Hiroshi Matsuo & Celia , 2017. "Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15024
    DOI: 10.1038/ncomms15024
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    Cited by:

    1. Qian Wang & Jie Yang & Zhicheng Zhong & Jeffrey A. Vanegas & Xue Gao & Anatoly B. Kolomeisky, 2021. "A general theoretical framework to design base editors with reduced bystander effects," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    2. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Atanu Maiti & Adam K. Hedger & Wazo Myint & Vanivilasini Balachandran & Jonathan K. Watts & Celia A. Schiffer & Hiroshi Matsuo, 2022. "Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Stefan Harjes & Harikrishnan M. Kurup & Amanda E. Rieffer & Maitsetseg Bayarjargal & Jana Filitcheva & Yongdong Su & Tracy K. Hale & Vyacheslav V. Filichev & Elena Harjes & Reuben S. Harris & Geoffrey, 2023. "Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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