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. 2011 Jul 3;475(7355):240-3.
doi: 10.1038/nature10162.

Architecture of the Mediator head module

Tsuyoshi Imasaki  1 , Guillermo Calero, Gang Cai, Kuang-Lei Tsai, Kentaro Yamada, Francesco Cardelli, Hediye Erdjument-Bromage, Paul Tempst, Imre Berger, Guy Lorch Kornberg, Francisco J Asturias, Roger D Kornberg, Yuichiro Takagi
Affiliations

Architecture of the Mediator head module

Tsuyoshi Imasaki et al. Nature. .

Abstract

Mediator is a key regulator of eukaryotic transcription, connecting activators and repressors bound to regulatory DNA elements with RNA polymerase II (Pol II). In the yeast Saccharomyces cerevisiae, Mediator comprises 25 subunits with a total mass of more than one megadalton (refs 5, 6) and is organized into three modules, called head, middle/arm and tail. Our understanding of Mediator assembly and its role in regulating transcription has been impeded so far by limited structural information. Here we report the crystal structure of the essential Mediator head module (seven subunits, with a mass of 223 kilodaltons) at a resolution of 4.3 ångströms. Our structure reveals three distinct domains, with the integrity of the complex centred on a bundle of ten helices from five different head subunits. An intricate pattern of interactions within this helical bundle ensures the stable assembly of the head subunits and provides the binding sites for general transcription factors and Pol II. Our structural and functional data suggest that the head module juxtaposes transcription factor IIH and the carboxy-terminal domain of the largest subunit of Pol II, thereby facilitating phosphorylation of the carboxy-terminal domain of Pol II. Our results reveal architectural principles underlying the role of Mediator in the regulation of gene expression.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Overall structure of the Mediator Head module
(a) Head module subunits domains. Med17 is shown in blue, Med11 in purple, Med22 in dark green, Med6 in yellow, Med8 in red, Med18 in cyan, and Med20 in orange. The region not modeled is shaded in gray, the region not present in the crystal is in white. Positions of med6 ts mutations are marked by arrows colored in green, srb suppressor mutations in blue, Med11 residue 47 (T) in white. NTD: N-terminal domain, BD: Bundle domain, CTD: C-terminal domain. (b) A ribbon model of the Mediator Head module is superimposed on the experimental electron density map contoured at 1.5 σ.
Figure 2
Figure 2. Mechanism of Mediator Head module complex assembly
Models of the Mini (Med17, Med11 and Med22) and Core (Mini module with Med6 and Med8) Head module as derived from our crystal structure of the full Head module (Core module with Med18 and Med20) are depicted for comparison. Schematic diagrams of Head module components (panel left) and corresponding structures (right) are shown.
Figure 3
Figure 3. Structures of Fixed and Movable jaw domains
(a) Fixed jaw domain interactions. The linker region of Med17 (320-420), Med11 (94-110), and Med22 (87-100) are drawn as dotted lines. (b) Movable jaw domain interactions. Linker regions of Med8 and Med11 are drawn as dotted lines. (c) Electron density map at the central Joint region, displaying density corresponding to the linker regions of Med11, Med22, and Med17. (d) Electron density map at the junction of Med11, Med22, and Med18 subunits. The models of Med22 BH1, Med11 BH1, BH2 and Med18 loop (residues 17-27, 281-289) are superimposed.
Figure 4
Figure 4. Structure of the Neck domain, and model of Head-Pol II-IIH
(a) The Neck domain is depicted from front, back (upper right), and top views (bottom right). (b) Model of Pol II-Mediator-TFIIH complex. Pol II and the Head structures were docked into the EM map of the Mediator-Pol II shown as a mesh . Head module is colored as in (Figure 1b). Core Pol II in brown, Rpb4/Rpb7 in purple, the Pol II CTD drawn as a black dotted line, TFIIH illustrated in a schematic representation (light blue). Location of Med11 residue 47 (T) is indicated.
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