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Review
. 2011 Oct 1;439(1):15-25.
doi: 10.1042/BJ20110972.

Gene-specific transcription activation via long-range allosteric shape-shifting

Chung-Jung Tsai  1 , Ruth Nussinov
Affiliations
Review

Gene-specific transcription activation via long-range allosteric shape-shifting

Chung-Jung Tsai et al. Biochem J. .

Abstract

How is specificity transmitted over long distances at the molecular level? REs (regulatory elements) are often far from transcription start sites. In the present review we discuss possible mechanisms to explain how information from specific REs is conveyed to the basal transcription machinery through TFs (transcription factors) and the Mediator complex. We hypothesize that this occurs through allosteric pathways: binding of a TF to a RE results in changes in the AD (activation domain) of the TF, which binds to Mediator and alters the distribution of the Mediator conformations, thereby affecting transcription initiation/activation. We argue that Mediator is formed by highly disordered proteins with large densely packed interfaces that make efficient long-range signal propagation possible. We suggest two possible general mechanisms for Mediator action: one in which Mediator influences PIC (pre-initiation complex) assembly and transcription initiation, and another in which Mediator exerts its effect on the already assembled but stalled transcription complex. We summarize (i) relevant information from the literature about Mediator composition, organization and structure; (ii) Mediator interaction partners and their effect on Mediator conformation, function and correlation to the RNA Pol II (polymerase II) CTD (C-terminal domain) phosphorylation; and (iii) propose that different allosteric signal propagation pathways in Mediator relate to PIC assembly and polymerase activation of the stalled transcription complex. The emerging picture provides for the first time a mechanistic view of allosteric signalling from the RE sequence to transcription activation, and an insight into how gene specificity and signal transmission can take place in transcription initiation.

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Figures

Figure 1
Figure 1. Simplified illustrations depict distinct stages of RNA Pol II transcription
(A) A possible nucleosome reordering process to make the unavailable promoter accessible. This is followed by PIC formation at the promoter region either via an activated recruitment or basal transcription accumulation. EC, elongation complex. (B) Atomic model of the PIC. The relative orientation between the TBP-bound DNA and Pol II is based on their interactions with TFIIB. The signature of transcription initiation is the formation of a transcription bubble with the DNA duplex melting in the Pol II active-site cleft. (C) Atomic model of the open PIC with the melted DNA drawn as broken lines. The open PIC complex then enters the elongation initiation stage to synthesize the first RNA nucleotide. The PEC continues to synthesize the nascent RNA and at a certain RNA length it dissociates from the promoter and leaves the scaffold for another quick re-initiation. At this stage, a mature EC completes the transcription, or a paused EC (not shown in the Figure) stalls at a proximal promoter region, waiting to be activated to resume transcription elongation. Pol II nomenclature is provided in [91,92].
Figure 2
Figure 2. Schematic diagram illustrating two distinct mechanisms of transcription signal transduction from TF via Mediator to the transcription machinery
In mechanism I (A), the DNA-bound TF binds Mediator which in turn recruits GTFs/Pol II to complete transcription without interruption. In mechanism II (B), a stalled PEC resumes its processive elongation from a paused stage after the DNA-bound TF binds with Mediator. We assume that the RE is exposed and available for TF binding in both mechanisms, and that the core promoter may be available (nucleosome free) or unavailable for access in mechanism I but is always available in mechanism II. For simplicity and clarity only two GTFs (TFIIH and TBP), Pol II, Mediator, Spt5, NELF and TF are included in the drawing instead of all PEC members. Mechanism I denotes the concept that, following a binding event of the TF DNA-binding domain to the RE, the TF AD recruits Mediator through binding at the Tail/Middle modules. In contrast, in mechanism II PEC already occupies the promoter. After TF binds the RE, it binds to Mediator at the Head/Middle modules and the transcription signal which originates from the TF–RE interaction propagates through Mediator’s Head to Pol II to disassociate NELF and enter processive elongation.
Figure 3
Figure 3. Schematic two-dimensional organization map of the yeast Mediator and Pol II
The numbers relate to Mediator and Pol II subunits. The broken lines are disordered linkers. This organization is based on experimental data from crystal structures (subunits MED8–MED18–MED20 [36,37], MED7–MED31 and MED7–MED21 [38]); EM (Head module, [25,27]), the Middle and Tail modules have been described in previous studies [41,100]. The relative orientation between Mediator and Pol II has been described previously [108]. Pol II Rpb4/Rpb7 and Clamp bind the Mediator Head module and the Pol II CTD binds the Middle module. In mechanism I, PEC formation is triggered by a TF AD-bound Mediator which interacts with Pol II (red) mostly via its Tail (pink) or Middle (blue) modules. In mechanism II, PEC is pre-assembled on the promoter and consequently there is a low level of Ser5 CTD phosphorylation. In both mechanisms, the recruitment of p-TEFb is needed to promote processive elongation after the RNA capping checkpoint. We speculate that the perturbation by AD binding to the Mediator Head module (green) causes a significant conformational change which propagates via MED17, MED18 and MED20 to Rpb4/Rpb7 and finally to the Clamp of Pol II. This propagation displaces NELF and facilitates the transition of a stalled PEC into an elongation phase. A large conformational change displayed by a sufficiently high population of Mediator will present ‘shape-shifting’. This map is for yeast; however, the human map is similar. The cartoon does not reflect the actual size of each of the Mediator subunits.
Figure 4
Figure 4. Protein–protein interfaces of Mediator complexes whose X-ray structures are available
Mediator is a very large multi-protein complex composed of 10–25 subunits. High-resolution structural information on Mediator is extremely limited to small domain–domain interactions or small subunits, all of which constitutes only tiny fractions of a large complex. Protein complexes are represented as ribbons in two light colours with the interface highlighted in dark colours. Only interfacial side chains are shown in space-fill with hydrophobic residues coloured orange and hydrophilic residues in cyan. All three interfaces, MED18/20 (PDB code 2HZM), MED7C/21 (PDB code 1YKE), MED7N/31 (PDB code 3FBI), and MED11/22 (PDB code 3R84), clearly show the domination of hydrophobic interactions which reflect the characteristics of a two-state protein folding. In turn, this explains the specificity and the disorder nature of individual Mediator subunits. Folding-upon-binding transitions of disordered states lead to specific interactions and efficient signal propagation across interfaces, which is particularly important for large multi-chain complexes. Efficient signalling may explain why Mediator subunits are highly disordered. This Figure is available as an interactive three-dimensional structure at http://www.BiochemJ.org/bj/439/0015/bj4390015add.htm.
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