The Mediator complex and the role of protein-protein interactions in the gene regulation machinery

At the core of gene regulation, a complex network of dynamic interactions between proteins, DNA and RNA has to be integrated in order to generate a binary biological output. Large protein complexes, called adaptors, transfer information from the transcription factors to the transcription machinery [1,2]. Here we focus on Mediator, one of the largest adaptor proteins in humans [3]. Assembled from 30 different subunits, this system provides extraordinary illustrations for the various roles played by protein-protein interactions. Recruitment of new subunits during evolution is an adaptive mechanism to the growing complexity of the organism. Integration of information happens at multiple scales, with allosteric effects at the level of individual subunits resulting in large conformational changes. Mediator is also rich in disordered regions that increase the potential for interactions by presenting a malleable surface to its environment. Potentially, 3000 transcription factors can interact with Mediator and so understanding the molecular mechanisms that support the processing of this overload of information is one of the great challenges in molecular biology.