Abstract
A large body of evidence accumulating in the past few years indicates the physiological significance of non-histone proteins lysine methylation, catalyzed by protein lysine methyl transferases (PKMTs). Dysregulation of these enzymes was shown to contribute to the development and progression of numerous diseases. SETD6 lysine methylatransferase was recently shown to participate in essential cellular processes, such as the NFkB pathway, oxidative stress and also the Wnt signaling cascade. In order to test the effect of blocking SETD6 catalytic activity, we used the peptide inhibition method, which is considered highly specific and can potentially target almost any protein. We designed a 15 amino acids peptide based on the sequence of the RelA protein (residues 302-316), containing the lysine that is methylated by SETD6. To enable cellular intake, the designed peptide was fused to a cell penetrating peptide (CPP) vp22. The vp22-RelA302-316 peptide showed direct and specific interaction with SETD6 in vitro. This interaction was shown to inhibit SETD6 methyltransferase activity. SETD6 catalytic blockage by the peptide was also observed in cells upon treatment with the vp22-RelA302-316, resulting in induced cellular migration and proliferation. This new insight into the activity of a methylation inhibitory peptide could represent a milestone in the development of therapeutic tools, which can be of use in physiological cases where administration of cell proliferation is required.
Highlights
Post-translational modifications (PTMs) contribute significantly to the structural and functional diversity of the proteins
A large body of evidence accumulating in the past few years indicates the physiological significance of non-histone proteins lysine methylation, catalyzed by protein lysine methyl transferases (PKMTs)
Growing amount of studies have shown that dysregulation of PKMTs has substantial roles in tumorigenesis [4], and efforts have been put in elucidating substrate specificity of these enzymes
Summary
Post-translational modifications (PTMs) contribute significantly to the structural and functional diversity of the proteins. These modifications confer complexity to the eukaryotic proteomes that is several orders of magnitude greater than the coding capacity of the genome [1]. Due to their pivotal role in physiological processes, in-depth understanding of protein PTMs is important for gaining a perception of a wide array of cellular functions and towards developing drug therapies for many lifethreatening diseases [2]. Growing amount of studies have shown that dysregulation of PKMTs has substantial roles in tumorigenesis [4], and efforts have been put in elucidating substrate specificity of these enzymes
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