*2.3. Post-Translational Modifications (PTMs)*

Phosphorylation is important for modulating the balance of proteins between the bound and unbound states, and previous studies reported that kinases target disordered proteins as many as twice, on average, the number of times they target structured proteins [42,43]. In this study, we predicted PTM (phosphorylation) sites in chordate sequences of MeCP2, CDKL5, and FOXG1 and predicted the conserved human phosphorylation sites to chordates in order to investigate the dynamics of their phosphorylation-related function. We found numerous conserved phosphorylation sites including 60/82 in CDKL5, 30/45 in MeCP2, and all 23 sites in FOXG1 in human (Figure 2 green lines and Supplementary Table S3). Most predicted human phosphorylation sites in MeCP2, CDKL5, and FOXG1 are conserved across chordates and are located in disordered regions; one exception is FOXG1, in which almost half of the phosphorylation sites are located in predicted ordered regions; structural disorder makes such sites accessible for phosphorylation. As PTMs affect the stability, turnover, interaction potential, and localization of proteins within the cell, proteins with disordered regions are more likely to be multifunctional [26]; accordingly, it has shown that MeCP2, CDKL5, and FOXG1 play multiple roles in the molecular basis.
