Complex regulatory mechanisms mediated by the interplay of multiple post-translational modifications

Post-translational modifications (PTMs), which are found largely in intrinsically disordered protein regions (IDRs), regulate protein activity, stability and interactions with partners. They are therefore critical for controlling essentially all cellular processes. A single modification event can have dramatic effects; however, proteins are often modified on multiple sites to collectively modulate the biological outcome. Multiple PTMs can mediate the same, complementary or opposing effects and the result of their interplay is determined by a complex combination of the number, positioning and type of modifications. Multiple PTMs can also synergize to shift the conformational or binding equilibria of the modified protein to modulate its interaction with partners or formation of higher order assembly. Recognition of such PTM crosstalk is crucial for understanding the underlying mechanisms of complex regulatory processes.