Photoregulation of PRMT-1 Using a Photolabile Non-Canonical Amino Acid.

Elizabeth A King,Douglas D Young,Diya M Uthappa,Anna K Martin,Cameron M Goff,Jordan K Villa,Naya K Burrow,Emily M Peairs,Rebecca T Deitch

doi:10.3390/molecules26165072

Elizabeth A King, Douglas D Young + Show 7 more

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https://doi.org/10.3390/molecules26165072

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Abstract

Protein methyltransferases are vital to the epigenetic modification of gene expression. Thus, obtaining a better understanding of and control over the regulation of these crucial proteins has significant implications for the study and treatment of numerous diseases. One ideal mechanism of protein regulation is the specific installation of a photolabile-protecting group through the use of photocaged non-canonical amino acids. Consequently, PRMT1 was caged at a key tyrosine residue with a nitrobenzyl-protected Schultz amino acid to modulate protein function. Subsequent irradiation with UV light removes the caging group and restores normal methyltransferase activity, facilitating the spatial and temporal control of PRMT1 activity. Ultimately, this caged PRMT1 affords the ability to better understand the protein’s mechanism of action and potentially regulate the epigenetic impacts of this vital protein.

Highlights

Post-translational modifications greatly expand the abilities of enzymes, depending on the chemical properties or conformational changes caused by the newly introduced functionality [1]
In order to prepare the caged PRMT1, ONBY was synthesized according to previously reported synthetic protocol under light-free conditions
The use of non-canonical amino acids (ncAAs) allows for site-specific incorporation, which provides a sophisticated level of control of protein function

Summary

Introduction

Post-translational modifications greatly expand the abilities of enzymes, depending on the chemical properties or conformational changes caused by the newly introduced functionality [1]. Protein methyltransferases catalyze the methylation of proteins at the positively charged amino acids’ lysine and arginine by transferring a methyl group from the cofactor S-adenosylL -methionine (SAM) [2,3]. This methylation is especially prevalent in the modification of gene regulation via protein/histone arginine methyltransferases (PRMTs) [1,2,3,4,5,6]. Chromatin methylation patterns affect gene expression, mitosis, genome stability and DNA repair mechanisms, but are relevant in disease pathogenesis. The PRMT family of methyltransferases is responsible for the regulation of a variety of cellular mechanisms, such as protein localization, cell fate, and cell signaling [5,6,9,10]

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