Modulating enzyme activity and specificity by preinstalled posttranslational modifications on substrates: PTM-induced...

Posttranslational modifications (PTM) (including, but not limited to, acetylation, methylation, ubiquitylation, SUMOylation, and phosphorylation) offer one of the key regulatory mechanisms available to the cell. Histone PTMs catalyzed by histone modifying enzymes are perhaps the most studied PTMs in the last two decades and are known to play a critical role in regulation of gene expression. There is extensive cross talk among different PTMs that affects activity and specificity of histone modifying enzymes, but deciphering mechanism and process by which PTMs are written and modified has proved to be challenging without understanding key underlying principles. Therefore, exploration of how PTMs are written under influence of existing PTMs (e.g., on histone) as well as general mechanisms governing their cross talk are of fundamental importance. In this review article, we examine and analyze some previous results that show that preinstalled PTMs on substrates (e.g., modified peptides or nucleosomes) can stimulate the activity and change the specificity of histone-modifying enzymes for installing new PTMs. We call such stimulation effects PTM-induced substrate-assisted stimulations and discuss some possible origins of such stimulations in certain cases. The possible role of water molecules in PTM cross talk in the nucleosome context is also discussed. Although the focus of this review article is mainly on some of the cross talk involving histone methylation stimulated by preinstalled methylation, acetylation, or ubiquitylation, the PTM-induced substrate-assisted stimulations also exist in some other PTM cross talk, and PTM-induced inhibition can be present as well. PTM-induced stimulations or inhibitions of enzyme activity may provide a unique way and attractive mechanism for regulation and signaling, but detailed studies are still necessary to fully understand how the stimulations/inhibitions are created and translated into altered activities and specificity for histone-modifying enzymes or some other systems.