Modulating protein-DNA interactions by post-translational modifications at disordered regions.

Intrinsically disordered regions, particularly disordered tails, are very common in DNA-binding proteins (DBPs). The ability of disordered tails to modulate specific and nonspecific interactions with DNA is tightly linked to their being rich in positively charged residues that are often non-randomly distributed along the tail. Perturbing the composition and distribution of charged residues in the disordered regions by post-translational modifications, such as phosphorylation and acetylation, may impair the ability of the tail to interact nonspecifically with DNA by reducing its DNA affinity. In this study, we analyzed datasets of 3398 and 8943 human proteins that undergo acetylation or phosphorylation, respectively. Both modifications are common on the disordered tails of DBPs (3.1 ± 0.2 (0.07 ± 0.007) and 2.0 ± 0.2 (0.02 ± 0.003) acetylation and phosphorylation sites per tail (per tail residue), respectively). Phosphorylation sites are abundant in disordered regions and particularly in flexible tails for both DBPs and non-DBPs. While acetylation sites are also frequently occurred in the disordered tails of DBPs, in non-DBPs they are often found in ordered regions. This difference may indicate that acetylation has different function in DBPs and non-DBPs. Post-translational modifications, which often take place at disordered sites of DBPs, can modulate the interactions of proteins with DNA by changing the local and global properties of the tails. The effect of the modulation can be tuned by adjusting the number of modifications and the cross-talks between them.