Evidence for a Strong Correlation Between Transcription Factor Protein Disorder and Organismic Complexity

Abstract

Studies of diverse phylogenetic lineages reveal that protein disorder increases in concert with organismic complexity but that differences nevertheless exist among lineages. To gain insight into this phenomenology, we analyzed all of the transcription factor (TF) families for which sequences are known for 17 species spanning bacteria, yeast, algae, land plants, and animals and for which the number of different cell types has been reported in the primary literature. Although the fraction of disordered residues in TF sequences is often moderately or poorly correlated with organismic complexity as gauged by cell-type number (r2 < 0.5), an unbiased and phylogenetically broad analysis shows that organismic complexity is positively and strongly correlated with the total number of TFs, the number of their spliced variants and their total disordered residues content (r2 > 0.8). Furthermore, the correlation between the fraction of disordered residues and cell-type number becomes stronger when confined to the TF families participating in cell cycle, cell size, cell division, cell differentiation, or cell proliferation, and other important developmental processes. The data also indicate that evolutionarily simpler organisms allow for the detection of subtle differences in the conserved IDRs of TFs as well as changes in variable IDRs, which can influence the DNA recognition and multifunctionality of TFs through direct or indirect mechanisms. Although strong correlations cannot be taken as evidence for cause-and-effect relationships, we interpret our data to indicate that increasing TF disorder likely was an important factor contributing to the evolution of organismic complexity and not merely a concurrent unrelated effect of increasing organismic complexity.

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

“…A recent comprehensive analysis of over 6 million proteins characterized intrinsic disorder at proteomic and protein levels indicates that IDPs/IDRs are more abundant in eukaryotes and certain functions are exclusively implemented by IDPs/IDRs . The correlation between the organism complexity and the amount of intrinsic disorder are consistent with the extensive involvement of IDPs/IDRs in regulatory and signaling functions and the increased disorder content in eukaryotic proteomes might be used by nature to deal with the increased cellular complexity …”

“…In a comprehensive bioinformatics study carried out by Xie et al, a positive correlation between the functional annotation of the SwissProt database and the predicted intrinsic disorder has been found. Generally, IDPs/IDRs are enriched in proteins involved in signaling and regulatory functions, including transcription regulation, cell cycle, mRNA processing, scaffolding, and apoptosis . Consequently, dysregulation of IDPs/IDRs are associated with a variety of human diseases .…”

“…13 The correlation between the organism complexity and the amount of intrinsic disorder are consistent with the extensive involvement of IDPs/IDRs in regulatory and signaling functions and the increased disorder content in eukaryotic proteomes might be used by nature to deal with the increased cellular complexity. 12,14,15 IDPs/IDRs are involved in various biological functions. In a comprehensive bioinformatics study carried out by Xie et al, 16,17 a positive correlation between the functional annotation of the SwissProt database and the predicted intrinsic disorder has been found.…”

“…Generally, IDPs/IDRs are enriched in proteins involved in signaling and regulatory functions, including transcription regulation, cell cycle, mRNA processing, scaffolding, and apoptosis. 6,14,15,[18][19][20][21][22][23][24][25][26][27][28][29][30][31] Consequently, dysregulation of IDPs/IDRs are associated with a variety of human diseases. [32][33][34][35][36][37][38][39][40][41][42][43][44] Most recently, many IDPs/IDRs are found to be able to undergo liquid-liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo.…”

Cellular labelling favours unfolded proteins

“…Cellular complexity often arises from structurally disordered proteins [1][2][3][4] . Intrinsically disordered regions (IDRs) within proteins often overlap with sites of alternative splicing and post-translational modifications (PTMs).…”