Protein-protein interactions during transcription activation: the case of the Escherichia coli cyclic AMP receptor protein

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Abstract
The Escherichia coli cyclic AMP receptor protein (CRP) is a homodimeric transcription activator triggered by cyclic AMP. Escherichia coli contains more than 100 different promoters that can be activated by CRP: in most cases the CRP acts by making direct contact with RNA polymerase. Remarkably, there is considerable variation in the location of the DNA site for CRP from one CRP-dependent promoter to another. Genetic methods have been used to locate the activating regions of CRP that make contact with RNA polymerase at promoters of different architectures. At promoters where the DNA site for CRP is centred near to positions -61,-71 or -81 (i.e. 61, 71 or 81 base pairs upstream of the transcript startpoint, respectively), a single surface-exposed loop (Activating Region 1) in the downstream subunit of the CRP dimer makes contact with RNA polymerase. The contact site in RNA polymerase is located in one of the C-terminal domains of two RNA polymerase alpha subunits. At promoters where the DNA site for CRP is centred near to position -41, both subunits of the CRP dimer make contact with RNA polymerase via three separate surface exposed regions (Activating Regions 1, 2 and 3). At these promoters, where bound CRP overlaps with RNA polymerase-binding elements, the C-terminal domains of the polymerase alpha subunits are displaced and bind upstream of CRP. Activation at a number of E.coli promoters is dependent on binding of two CRP dimers, with one dimer bound near to position -41 and the other dimer bound further upstream. In these cases, both bound CRP dimers contact RNA polymerase. The CRP dimer bound around position -41 contacts RNA polymerase via Activating Regions 1, 2 and 3, whereas the upstream bound CRP dimer contacts one of the displaced alpha C-terminal domains via Activating Region 1 in the downstream CRP subunit. Thus in these cases, codependence on two activators is due to simultaneous contacts between separate activators and RNA polymerase. This mechanism allows great flexibility, as any activator that can contact the C-terminal domain of the RNA polymerase alpha subunits can act cooperatively with CRP.

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