In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment

Abstract

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting 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 investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order–disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT.

Genome-Wide Analysis of Whole Human Glycoside Hydrolases by Data-Driven Analysis in Silico

“…Long consecutively disordered residues (>30) may function as entropic chains or can be involved in interactions using combinations of recognition motifs or domains [33]. We previously reported that residues within disordered regions that function as entropic chains evolve quickly, whereas those involved in protein-protein interactions tend to be constrained [13,14]. Thus, it may be relevant for some ancient glycoside hydrolases to harbour long stretches of disordered regions because the conformational plasticity of these regions enables the recognition of or binding to multiple partners, which is beneficial for identifying misfolded proteins.…”

“…This is supported by comparison of evolutionary rates between ordered and disordered structured proteins. Disordered regions commonly evolve faster than ordered structures [10][11][12][13][14] because of differences in the relative constraints that maintain folding interactions [15]. However, there are exceptions to this rule.…”

“…However, there are exceptions to this rule. For instance, specific functional binding and modification regions of a disordered structure are constrained [13,14,16], thus introducing heterogeneity into evolutionary rates.…”

Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

“…Its placement in the molecular phylogenetic tree of protein kinases indicates identity with the CDK and mitogen-activated protein kinase (MAPK) families (Figure 1(a)) [28]. The catalytic domain of the CDKL5 enzyme has a characteristic 12-subdomain structure of Ser/Thr kinases, the sequence of which is highly conserved across many species, from mammals to fish (Figure 1(b)) [32][33][34]. An activation loop, which includes the TEY sequence observed in MAPK family kinases, is present between subdomains VII and VIII of the catalytic domain.…”

Macromolecular Interactions of Disordered Proteins

“…Fahmi, M. et al provided insight into the structural characteristics, evolution and interaction landscapes of those three proteins. They also reported the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT [35].…”