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NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity

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  • In-Ja L. Byeon

    (University of Pittsburgh School of Medicine
    Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine)

  • Jinwoo Ahn

    (University of Pittsburgh School of Medicine
    Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine)

  • Mithun Mitra

    (Section on Viral Gene Regulation, Program on Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Chang-Hyeock Byeon

    (University of Pittsburgh School of Medicine
    Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine)

  • Kamil Hercík

    (Section on Viral Gene Regulation, Program on Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
    Present address: Fraunhofer IME – Division Molecular Biology, Biological Operating Systems: Infectious Diseases, Forckenbeckstraβe 6, 52074 Aachen, Germany)

  • Jozef Hritz

    (University of Pittsburgh School of Medicine
    Present address: CEITEC, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic)

  • Lisa M. Charlton

    (University of Pittsburgh School of Medicine
    Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine)

  • Judith G. Levin

    (Section on Viral Gene Regulation, Program on Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Angela M. Gronenborn

    (University of Pittsburgh School of Medicine
    Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine)

Abstract

Human APOBEC3A is a single-stranded DNA cytidine deaminase that restricts viral pathogens and endogenous retrotransposons, and has a role in the innate immune response. Furthermore, its potential to act as a genomic DNA mutator has implications for a role in carcinogenesis. A deeper understanding of APOBEC3A’s deaminase and nucleic acid-binding properties, which is central to its biological activities, has been limited by the lack of structural information. Here we report the nuclear magnetic resonance solution structure of APOBEC3A and show that the critical interface for interaction with single-stranded DNA substrates includes residues extending beyond the catalytic centre. Importantly, by monitoring deaminase activity in real time, we find that A3A displays similar catalytic activity on APOBEC3A-specific TTCA- or A3G-specific CCCA-containing substrates, involving key determinants immediately 5′ of the reactive C. Our results afford novel mechanistic insights into APOBEC3A-mediated deamination and provide the structural basis for further molecular studies.

Suggested Citation

  • In-Ja L. Byeon & Jinwoo Ahn & Mithun Mitra & Chang-Hyeock Byeon & Kamil Hercík & Jozef Hritz & Lisa M. Charlton & Judith G. Levin & Angela M. Gronenborn, 2013. "NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2883
    DOI: 10.1038/ncomms2883
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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. 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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