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Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions
- Source :
- Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
- Publication Year :
- 2018
- Publisher :
- Nature Portfolio, 2018.
-
Abstract
- 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 structural preferences identified for A3A leads to a new paradigm for identifying A3A’s involvement in mutation of endogenous or exogenous DNA.
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 8
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Scientific Reports
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.0666f6b6aeeb4da28babab14046087f4
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41598-018-25881-z