Malleable machines take shape in eukaryotic transcriptional regulation

Abstract

Transcriptional control requires the spatially and temporally coordinated action of many macromolecular complexes. Chromosomal proteins, transcription factors, co-activators and components of the general transcription machinery, including RNA polymerases, often use structurally or stoichiometrically ill-defined regions for interactions that convey regulatory information in processes ranging from chromatin remodeling to mRNA processing. Determining the functional significance of intrinsically disordered protein regions and developing conceptual models of their action will help to illuminate their key role in transcription regulation. Complexes comprising disordered regions often display short recognition elements embedded in flexible and sequentially variable environments that can lead to structural and functional malleability. This provides versatility to recognize multiple targets having different structures, facilitate conformational rearrangements and physically communicate with many partners in response to environmental changes. All these features expand the capacities of ordered complexes and give rise to efficient regulatory mechanisms.

Figure 1

Schematic representation of the four main (highly interdependent) components of the eukaryotic transcription machinery. (a–d) Chromatin remodeling (a), transcription factors (b), co-activators (c) and basal machinery (d). Disordered histone (yellow) tails (dashed line) assist the assembly of nucleosomes and provide platforms for chromatin remodeling complexes. Chromatin remodeling complexes such as SWI/SNF regulate the accessibility of the DNA, and their mobility is enhanced by disordered regions. Transcription factors decipher regulatory information encoded in enhancer regions (UAS, upstream activating sequence), and they interact with other proteins via disordered TADs. Large co-activator complexes such as the Mediator (head, middle and tail modules are shown in orange, green and yellow, respectively) transmit signals from enhancer-and repressor-bound factors to the core machinery. Transcription initiation is achieved by RNAP II assisted by five general transcription factors (TFIIA, TFIIB, TFIIE, TFIIF and TFIIH). The disordered CTD of RNAP II serves as a scaffold for a range of complexes involved in different stages of transcription, and it functions in a phosphorylation-dependent manner.

Figure 2

Molecular recognition by intrinsically disordered proteins. (a) Binding of IDPs to their partners is often coupled to disorder-to-order transition. IDP segments might have transient secondary structures that are preserved in the bound state (preformed element, orange), whereas other segments may exhibit different conformations (yellow) with different partners (promiscuity). Owing to this segmental mode of binding, some parts of IDPs may remain disordered (fuzzy, dashed lines) in the bound state, which contributes to the multifunctionality (for example, moonlighting) of these proteins. (b) Disorder profile of the p53 transcription factor. p53 is at the center of a large signaling network regulating expression of genes involved in a variety of cellular processes, such as cell cycle progression, apoptosis induction, DNA repair and response to cellular stress. p53 interacts with a large number of other proteins, and the interaction sites are signaled by downward spikes in the plot of disorder. Disorder predictions were performed by PONDR VL-XT (http://www.pondr.com/); segments with scores above 0.5 correspond to disordered regions, while those below 0.5 correspond to ordered regions or binding sites. The structures of the complexes representing illustrative examples of various molecular recognition features (MoRFs) are displayed around the predicted disorder pattern.

Figure 3

Domain structure of CBP/p300 transcriptional co-activator and three-dimensional structures of complexes of globular CBP domains with disordered transcription factors bound. TAZ1 domain with HIF1-α (Protein Data Bank (PDB) code 1L8C) and CITED2 (PDB code 1R8U); KIX domain with KID of CREB (PDB code 1KDX) and cMyb (PDB code 1SB0); Bromo domain with p53 CTD (PDB code 1JSP); disordered NCBR domain with ACTR (PDB code 1KBH).