**5. Conclusions**

In the last two decades, effort on elucidating RTT has shown a promising trend towards developing a reliable treatment for this disorder. Given a similarity in IDR properties and several overlapping symptoms, we investigated the evolution of MeCP2, CDKL5, and FOXG1 disordered structures and their binding partners through prediction and phylogenetic profiling, respectively. Here, we provided insight to the structural characteristics, evolution and interaction landscapes of those three proteins related to RTT. We suggested that the disordered structures of MECP2, CDKL5, and FOXG1 contribute to the versatility in brain development and may play a crucial role in brain evolution in chordates. We hypothetically suggested that CDKL5 could be a potential target for RTT treatment, particularly by targeting its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with different structures of similar affinity. Finally, this study may provide valuable guidance for experimental research, particularly on the relationship between RTT and disordered regions.

**Supplementary Materials:** Supplementary materials can be found at http://www.mdpi.com/1422-0067/20/22/ 5593/s1.

**Author Contributions:** Conceptualization, M.F., Y.K. and M.I.; methodology, M.F., G.Y., Y.K. and M.I..; software, M.F. and G.Y.; validation, M.F., G.Y. and K.S.; formal analysis, M.F. and G.Y.; investigation, M.F., G.Y., K.S., S.K., T.K.-K., T.I., Y.K. and M.I.; resources, S.K, T.K.-K. and T.I.; data curation, M.F., Y.K. and M.I.; writing—original draft preparation, M.F..; writing—review and editing, S.K., T.K.-K., T.I., Y.K. and M.I.; visualization, M.F., G.Y. and K.S.; supervision, M.I.; project administration, M.I.; funding acquisition, T.I. and M.I.

**Funding:** This study was supported by the MEXT-supported program for the strategic research foundation at private universities (2015–2019 to T.I) and Takeda Science Foundation.

**Acknowledgments:** We would like to thank Takahiro Nakamura and Tadasu Shin-I for support and helpful comments.

**Conflicts of Interest:** The authors declare no competing interest.
