Malleable machines in transcription regulation

The Mediator complex

Ágnes Tóth-Petróczy, Christopher J. Oldfield, I. Simon, Yuichiro Takagi, A. Keith Dunker, Vladimir N. Uversky, M. Fuxreiter

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit transcriptional signals. Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules. The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size. IDRs can contribute to Mediator's function in three different ways: they can individually serve as target sites for multiple partners having distinctive structures; they can act as malleable linkers connecting globular domains that impart modular functionality on the complex; and they can also facilitate assembly and disassembly of complexes in response to regulatory signals. Short segments of IDRs, termed molecular recognition features (MoRFs) distinguished by a high protein-protein interaction propensity, were identified in 16 and 19 subunits of the yeast and human Mediator, respectively. In Saccharomyces cerevisiae, the functional roles of 11 MoRFs have been experimentally verified, and those in the Med8/Med18/Med20 and Med7/Med21 complexes were structurally confirmed. Although the Saccharomyces cerevisiae and Homo sapiens Mediator sequences are only weakly conserved, the arrangements of the disordered regions and their embedded interaction sites are quite similar in the two organisms. All of these data suggest an integral role for intrinsic disorder in Mediator's function.

Original languageEnglish
Article numbere1000243
JournalPLoS Computational Biology
Volume4
Issue number12
DOIs
Publication statusPublished - Dec 2008

Fingerprint

Mediator Complex
Mediator
Transcription
Yeast
Saccharomyces cerevisiae
transcription (genetics)
DNA-directed RNA polymerase
RNA Polymerase II
Proteins
tail
Molecular recognition
protein
yeasts
multiprotein complexes
Saccharomyces Cerevisiae
RNA
Yeasts
organisms
regulatory proteins
protein-protein interactions

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modelling and Simulation
  • Computational Theory and Mathematics

Cite this

Tóth-Petróczy, Á., Oldfield, C. J., Simon, I., Takagi, Y., Dunker, A. K., Uversky, V. N., & Fuxreiter, M. (2008). Malleable machines in transcription regulation: The Mediator complex. PLoS Computational Biology, 4(12), [e1000243]. https://doi.org/10.1371/journal.pcbi.1000243

Malleable machines in transcription regulation : The Mediator complex. / Tóth-Petróczy, Ágnes; Oldfield, Christopher J.; Simon, I.; Takagi, Yuichiro; Dunker, A. Keith; Uversky, Vladimir N.; Fuxreiter, M.

In: PLoS Computational Biology, Vol. 4, No. 12, e1000243, 12.2008.

Research output: Contribution to journalArticle

Tóth-Petróczy Á, Oldfield CJ, Simon I, Takagi Y, Dunker AK, Uversky VN et al. Malleable machines in transcription regulation: The Mediator complex. PLoS Computational Biology. 2008 Dec;4(12). e1000243. https://doi.org/10.1371/journal.pcbi.1000243
Tóth-Petróczy, Ágnes ; Oldfield, Christopher J. ; Simon, I. ; Takagi, Yuichiro ; Dunker, A. Keith ; Uversky, Vladimir N. ; Fuxreiter, M. / Malleable machines in transcription regulation : The Mediator complex. In: PLoS Computational Biology. 2008 ; Vol. 4, No. 12.
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