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

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.