Evolutionary Approach of Intrinsically Disordered CIP/KIP Proteins

Abstract

The mammalian CIP/KIP family proteins are intrinsically disordered proteins (IDPs) that can regulate various cellular processes. However, many reports have shown that IDPs generally evolve more rapidly than ordered proteins. Here, to elucidate the functional adaptability of CIP/KIP proteins in vertebrate, we analysed the rates of evolution in relation to their structural and sequence properties and predicted the post-translational modification based on the sequence data. The results showed that CIP/KIP proteins generally could maintain their function through evolution in the vertebrate. Basically, the disordered region that acts as a flexible linker or spacer has a conserved propensity for structural disorder and a persistent, fast rate of amino acid substitution, which could result in a significantly faster rate of evolution compared to the ordered proteins. Describing the pattern of structural order-disorder evolution, this study may give an insight into the well-known characteristics of IDPs in the evolution of CIP/KIP proteins.

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.…”

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

“…The flexible disorder has a constrained disordered structure despite having rapid evolution of residues; the amino acid substitutions of this property are constrained to residues that confer structural flexibility as the change from structurally disordered to ordered could affect protein function. This type of IDR typically functions as an entropic spring, flexible linker, or spacer without becoming structured and is frequently located outside the domain region [26,[35][36][37]. In contrast, constrained disorder is associated with protein-protein interaction interfaces that adopt a structured conformation or undergo folding upon binding and are thus constrained in terms of sequence, while still requiring flexibility.…”

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

“…Disordered regions commonly evolve faster than ordered structures [10][11][12][13] because of differences in the relative constraints that maintain folding interactions [14]. However, there are exceptions to this rule.…”