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Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B

Shurong Hou, Tania V. Slivas, Florian Leidner, Ellen A. Nalivaika, Hiroshi Matsuo, View ORCID ProfileNese Kurt Yilmaz, View ORCID ProfileCelia A. Schiffer
doi: https://doi.org/10.1101/304170
Shurong Hou
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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Tania V. Slivas
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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Florian Leidner
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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Ellen A. Nalivaika
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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Hiroshi Matsuo
2Basic Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
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Nese Kurt Yilmaz
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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  • ORCID record for Nese Kurt Yilmaz
Celia A. Schiffer
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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  • ORCID record for Celia A. Schiffer
  • For correspondence: Celia.Schiffer@umassmed.edu
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Abstract

APOBEC3s proteins (A3s), a family of human cytidine deaminases, protect the host cell from endogenous retro-elements and exogenous viral infections by introducing hypermutations. However, the ability to mutate genomic DNA makes A3s a potential cancer source. Of the 7 human A3s, A3B has been implicated as an endogenous cause for multiple cancers. Despite overall similarity, A3s have distinct deamination activity with A3B among the least catalytically active. Over the past few years, several structures of apo as well as DNA-bound A3 proteins have been determined. These structures revealed the molecular determinants of nucleotide specificity and the importance of the loops around the active site in DNA binding. However, for A3B, the structural basis for regulation of deamination activity and the role of active site loops in coordinating DNA had remained unknown. In this study, using a combination of advanced molecular modelling followed by experimental mutational analysis and dynamics simulations, we investigated molecular mechanism of A3B regulating activity and DNA binding. We identified a unique auto-inhibited conformation of A3B that restricts access and binding of DNA to the active site, mainly due to the extra PLV residues in loop 1. We modelled DNA binding to fully native A3B and found that Arg211 in the arginine patch of loop1 is the gatekeeper while Arg212 stabilizes the bound DNA. This model also identified the critical residues for substrate specificity, especially at the -1 position. Our results reveal the structural basis for relatively lower catalytic activity of A3B and provide opportunities for rational design of inhibitors that specifically target A3B to benefit cancer therapeutics.

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Posted April 18, 2018.
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Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B
Shurong Hou, Tania V. Slivas, Florian Leidner, Ellen A. Nalivaika, Hiroshi Matsuo, Nese Kurt Yilmaz, Celia A. Schiffer
bioRxiv 304170; doi: https://doi.org/10.1101/304170
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Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B
Shurong Hou, Tania V. Slivas, Florian Leidner, Ellen A. Nalivaika, Hiroshi Matsuo, Nese Kurt Yilmaz, Celia A. Schiffer
bioRxiv 304170; doi: https://doi.org/10.1101/304170

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