Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions.

Scientific Reports
Tania V SilvasCelia A Schiffer

Abstract

The APOBEC3 (A3) family of human cytidine deaminases is renowned for providing a first line of defense against many exogenous and endogenous retroviruses. However, the ability of these proteins to deaminate deoxycytidines in ssDNA makes A3s a double-edged sword. When overexpressed, A3s can mutate endogenous genomic DNA resulting in a variety of cancers. Although the sequence context for mutating DNA varies among A3s, the mechanism for substrate sequence specificity is not well understood. To characterize substrate specificity of A3A, a systematic approach was used to quantify the affinity for substrate as a function of sequence context, length, secondary structure, and solution pH. We identified the A3A ssDNA binding motif as (T/C)TC(A/G), which correlated with enzymatic activity. We also validated that A3A binds RNA in a sequence specific manner. A3A bound tighter to substrate binding motif within a hairpin loop compared to linear oligonucleotide, suggesting A3A affinity is modulated by substrate structure. Based on these findings and previously published A3A-ssDNA co-crystal structures, we propose a new model with intra-DNA interactions for the molecular mechanism underlying A3A sequence preference. Overall, the sequence and ...Continue Reading

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Citations

Mar 15, 2019·Journal of Molecular Endocrinology·Nicola J Smith, Timothy Robert Fenton
Jun 27, 2019·Protein Science : a Publication of the Protein Society·Tania V Silvas, Celia A Schiffer
Oct 12, 2019·Organic & Biomolecular Chemistry·Fareeda M BarzakElena Harjes
Aug 20, 2019·Nucleic Acids Research·William C SolomonHiroshi Matsuo
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Dec 10, 2020·Open Biology·Milaid Granadillo RodríguezLinda Chelico
Dec 23, 2020·PloS One·Yulong WeiXuhua Xia
Dec 17, 2020·Microorganisms·Yoshiyuki Hakata, Masaaki Miyazawa
May 18, 2021·The FEBS Journal·Alexander BotvinnikMoshe Kotler
Jun 26, 2021·The Journal of Biological Chemistry·Shurong HouCelia A Schiffer
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Aug 7, 2021·Trends in Genetics : TIG·Karla Cervantes-GraciaRichard Chahwan
Aug 22, 2018·ACS Chemical Biology·Manjuan LiuTeresa Kaserer
Aug 27, 2019·Biochemistry·Samantha J ZieglerYong Xiong
Nov 21, 2018·Journal of Chemical Theory and Computation·Shurong HouCelia A Schiffer

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Methods Mentioned

BETA
NMR
deamination

Software Mentioned

Topspin
Prism
ProteinPrep Wizard in Maestro
GraphPad

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