Understanding large multiprotein complexes: applying a multiple allosteric networks model to explain the function of the Mediator transcription complex

Abstract

SummaryThe regulation of transcription and of many other cellular processes involves large multi-subunit protein complexes. In the context of transcription, it is known that these complexes serve as regulatory platforms that connect activator DNA-binding proteins to a target promoter. However, there is still a lack of understanding regarding the function of these complexes. Why do multi-subunit complexes exist? What is the molecular basis of the function of their constituent subunits, and how are these subunits organized within a complex? What is the reason for physical connections between certain subunits and not others? In this article, I address these issues through a model of network allostery and its application to the eukaryotic RNA polymerase II Mediator transcription complex. The multiple allosteric networks model (MANM) suggests that protein complexes such as Mediator exist not only as physical but also as functional networks of interconnected proteins through which information is transferred from subunit to subunit by the propagation of an allosteric state known as conformational spread. Additionally, there are multiple distinct sub-networks within the Mediator complex that can be defined by their connections to different subunits; these sub-networks have discrete functions that are activated when specific subunits interact with other activator proteins.

The Mediator complex and transcription regulation

“…The scope of the structural changes imply a coordinated set of movements among numerous (perhaps a majority) Mediator subunits. Such coordination has been described with a multiple allosteric network model, in which a structural shift at one site propagates throughout a network of protein subunits (Lewis, 2010 ). This model also suggests how an interconnected protein network such as Mediator could enable such dramatic structural transitions in the absence of ATP hydrolysis (Bray & Duke, 2004 ).…”

Allosteric conformational ensembles have unlimited capacity for integrating information

“…The collective effect of these coupled dynamics is difficult to predict but we can hazard some guesses. It has been suggested, for example, that multi-protein complexes like Mediator couple the conformational repertoires of their components proteins into complex allosteric networks for processing information (Lewis, 2010).…”