Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Phylogenetic Profiling and Disordered Region Assessment of MECP2, CDKL5, and FOXG1 to Reveal Strategies for Rett Syndrome Treatment

Muhamad Fahmi
ORCID logo ,
Gen Yasui
,
Kaito Seki
,
Syouichi Katayama
,
Takako Kaneko-Kawano
,
Tetsuya Inazu
,
Yukihiko Kubota
,
Masahiro Ito
*
Version 1 : Received: 4 November 2019 / Approved: 6 November 2019 / Online: 6 November 2019 (10:58:54 CET)

A peer-reviewed article of this Preprint also exists.

Fahmi, M.; Yasui, G.; Seki, K.; Katayama, S.; Kaneko-Kawano, T.; Inazu, T.; Kubota, Y.; Ito, M. In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment. Int. J. Mol. Sci. 2019, 20, 5593. Fahmi, M.; Yasui, G.; Seki, K.; Katayama, S.; Kaneko-Kawano, T.; Inazu, T.; Kubota, Y.; Ito, M. In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment. Int. J. Mol. Sci. 2019, 20, 5593.

Abstract

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which alter the functions of domains to either bind to methylated DNA or interact with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We tried to elucidate RTT through evolution and structure assessment of MeCP2, CDKL5, and FOXG1, by focusing on their binding partners and disordered structures. Here, we provide insight into the similarities of the FOXG1 and MECP2 binding partners evolution and function. On the other hand, we suggest that CDKL5 could be a potential candidate for a classical RTT treatment, particularly based on its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with divergent structures of similar affinity. Additionally, we provide insight into the relationship between disordered structure and disease.

Keywords

rett syndrome; intrinsically disordered region; phylogenetic profile analysis; post-transcriptional modification; methyl-cpg-binding protein 2; cyclin-dependent kinase-like 5; forkhead box protein g1

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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