Zinc enhancement of cytidine deaminase activity highlights a potential allosteric role of loop-3 in regulating APOBEC3 enzymes

Ailie Marx,Akram Alian,Meytal Galilee

doi:10.1038/srep18191

Ailie Marx, Akram Alian + Show 1 more

Open Access

https://doi.org/10.1038/srep18191

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Journal: Scientific Reports	Publication Date: Dec 18, 2015
Citations: 14	License type: CC BY 4.0

Affiliation: Technion – Israel Institute of Technology

Abstract

The strong association of APOBEC3 cytidine deaminases with somatic mutations leading to cancers accentuates the importance of their tight intracellular regulation to minimize cellular transformations. We reveal a novel allosteric regulatory mechanism of APOBEC3 enzymes showing that APOBEC3G and APOBEC3A coordination of a secondary zinc ion, reminiscent to ancestral deoxycytidylate deaminases, enhances deamination activity. Zinc binding is pinpointed to loop-3 which whilst highly variable harbors a catalytically essential and spatially conserved asparagine at its N-terminus. We suggest that loop-3 may play a general role in allosterically tuning the activity of zinc-dependent cytidine deaminase family members.

Highlights

Biology is written in a four-letter nucleotide alphabet that is enriched by a myriad of modifications
apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) proteins are not exclusive in their ability to deaminatenucleotides, forming part of a much wider superfamily of zinc-dependent deaminases including enzymes which convert adenosine to inosine and act on either tRNA or mRNA
In addition to the polynucleotide substrates targeted by the APOBECs, this superfamily includes cytidine deaminases (CDA’s), which act on free cytidine, and deoxycytidylate deaminases that deaminate cytidine monophosphate, both enzymes being involved in pyrimidine synthesis

Summary

Introduction

Biology is written in a four-letter nucleotide alphabet that is enriched by a myriad of modifications. A structural description of a polynucleotide bound APOBEC has remained elusive, it is presumed that the differences in substrate recognition among the family members are mainly a result of the length, composition and position of the loops surrounding the catalytic site: Loop-7 plays an important role in DNA substrate specificity and recognition and loop-1 being widely open in polynucleotide-deaminases allowing for the binding of larger substrates[3,4,5,7,8,11,12,13].

Results

Conclusion