Intrinsic disorder within and flanking the DNA-binding domains of human transcription factors

Abstract

While the term 'protein structure' is commonplace, it is increasingly appreciated that proteins may not possess a single, well-defined structure: some regions of proteins are intrinsically disordered. The role these intrinsically disordered regions (IDRs) play in protein function is an area of significant interest. In particular, because proteins containing IDRs are largely involved in processes related to molecular recognition, the question arises whether IDRs are important in these recognition events. It has been observed that IDRs are enriched in transcription factors (TFs) in comparison with other proteins, and we sought to explore this enrichment more precisely, with an eye toward functional dissection of the prevalence and locations of IDRs in different classes of TFs. Specifically, we considered the occurrences of 76 classes of DNA-binding domains (DBDs) within a comprehensive set of 1,747 human, sequence-specific TFs. For each DBD class, we analyzed whether a significant level of disorder was present within the DBD itself, the N-terminal or C-terminal sequence flanking the DBD, or both flanking sequences. We found that although the DBDs themselves exhibit significant order, the regions flanking the DBDs exhibit significant disorder, which suggests a functional role for such IDRs in TF DNA binding. These results may have important implications for studies of TFs not just in human but across all eukaryotes, and suggest future studies focused on testing the roles of N- and C-terminal flanking regions in determining or modulating the DNA binding affinity and/or specificity of the associated TFs.

Fig. 1

(A) A schematic of the pipeline for generating the TF set and the non-TF control set. (B) Sequence length distributions of the TF set (nr TFs), the non-TF control set, and the set of all human TFs (with redundancy). (C) The amino acid compositions of the TF set, the non-TF control set, and the set of all human TFs. Amino acids are listed from most order-promoting to most disorder-promoting, according to [13]. It is apparent from the histogram that compared to proteins in general, TFs have fewer order-promoting residues (e.g., W, F, Y, I, M, L, V) and more disorder-promoting residues (e.g., P, E, S, K, Q, H).

Fig. 2

Distributions of the fraction of each protein's residues predicted as disordered by each method for the proteins in (A) the TF set and (B) the non-TF control set.

Fig. 3

Shown are meta-plots for five prevalent DBDs in human TFs. (A) zinc-finger C2H2-type (length: ~23 amino acids), (B) zinc-finger C2HC-type (length: ~31 amino acids), (C) zinc-finger C4-type (length: ~70 amino acids), (D) homeodomain fold (length: ~58 amino acids), and (E) helix-loop-helix (length: ~53 amino acids).