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First published online August 13, 2003
doi: 10.1242/10.1242/jcs.00734

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The mediator coactivator complex: functional and physical roles in transcriptional regulation

¹ Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
² Department of Biochemistry, Division of Nucleic Acids Enzymology, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA

View larger version (40K): [in a new window]   Fig. 1. The yeast mediator model of activator-dependent transcription. Shown is a hypothetical promoter containing a canonical TATA box and interacting with the TFIID complex. Additional TFIID contacts are made with the initiator element (at the start site) and downstream of the start site. The arrow within the TFIID complex represents the start site of transcription. The three activators (GCN4, VP16 and GAL4) are shown binding to their DNA sites and recruiting yeast mediator to the promoter via a physical interaction with a mediator module (indicated by the overlap between the activator and the respective mediator module) (Koh et al., 1998; Lee et al., 1999b). Additional overlap among the three yeast mediator modules represents physical interactions between the three modules. Lastly, overlap/physical interactions between the MED9/MED10 and SRB4 modules and RNA polymerase II are illustrated (Kang et al., 2001). The HEAD, MIDDLE and TAIL domains are indicated and are based on recent structural data (Asturias et al., 1999; Davis et al., 2002; Dotson et al., 2000b). Note that the negative regulation of TFIIH CAK (cyclin H/cdk7) by the SRB10/SRB11 (cyclin-C-CDK8) is specific to human and has not been observed in yeast (Akoulitchev et al., 2000).

View larger version (63K): [in a new window]   Fig. 2. Conformations of the mammalian mediator complexes. (A) EM composites of the ARC-L and CRSP complexes, which illustrate the size and structural differences between the two. (B) EM composites showing the distinctly different structural conformations adopted by CRSP when isolated via affinity interactions with either the VP16 or SREBP activator. EM composites were generously provided by Dylan Taatjes and Bob Tjian (Naar et al., 2002; Taatjes et al., 2002).

View larger version (38K): [in a new window]   Fig. 3. A model of mediator function. This schematic model suggests that particular combinations of activators play a role in influencing the conformation of mediator. These different conformations would influence the re-entry of RNA polymerase II to the promoter to initiate subsequent rounds of transcription. The combination of activators in panel A forces a mediator conformation that only promotes the slow re-entry of RNA polymerase II to the promoter, while the combination in panel B promotes a faster RNA polymerase II re-entry via a more productive interaction with mediator. It is important to note that activator A, in the context of a different set of activators (X and Y in panel B), is capable of inducing a different conformation of mediator (Lefstin and Yamamoto, 1998). This is not meant to suggest that the number of activators is the key point in inducing a particular mediator conformation.