Catabolite Activator Protein

How CAP works

CAP can activate transcription at more than 100 catabolite-sensitive operons. In the presence of cAMP, CAP binds to specific sites on the DNA in order to promote the binding and function of RNAP. CAP-dependent promoters have been divided into three classes, based on the mechanism of action of CAP at each promoter.

Class I CAP-dependent promoter activation: CAP dimer interacting with the aCTD of RNAP, which is also comprised of b and s subunits

Courtesy of Richard Ebright, Journal of Molecular Biology 293, S. Busby and R. Ebright, Transcription Activation by Catabolite Activator Protein (CAP), 199-213 (1999), PMID: 10550204

Transcription activation at class I CAP-dependent promoters involves the simplest mechanism of CAP gene activation. A CAP dimer binds to a single DNA site that is upstream of the RNAP-binding promoter region (which involves DNA sites at positions –35 and –10 from the transcription start site). The AR1 region of CAP (shown as the broken circle in the diagram above) interacts with the aCTD of RNAP, which facilitates the binding of RNAP to the promoter DNA to form the RNAP-promoter closed complex, resulting in an increase in transcription initiation. Once the RNAP-promoter closed complex is formed, the presence of CAP is no longer required. An example of a class I CAP-dependent promoter is the lac promoter, which controls the production of lactose-degrading enzymes from the lac operon.

Class II CAP-dependent promoter activation: CAP dimer interacting with the aCTD and aNTD of RNAP

Courtesy of Richard Ebright, Journal of Molecular Biology 293, S. Busby and R. Ebright, Transcription Activation by Catabolite Activator Protein (CAP), 199-213 (1999), PMID: 10550204

Transcription activation at class II CAP-dependent promoters also involves the binding of CAP to a single DNA site, but this site overlaps with the RNAP-binding promoter region, unlike with class I promoters which bind CAP upstream of where RNAP binds. Class II transcription activation involves two interactions with the RNAP alpha subunit: AR1 of the upstream subunit of the CAP dimer binds to the aCTD of RNAP in order to promote RNAP-promoter closed complex formation; AR2 of the downstream subunit of the CAP dimer binds to the aNTD of RNAP, which promotes the isomerization of the closed RNAP-promoter complex to an open complex. In some cases, the AR3 region of CAP is also involved in gene activation at class II promoters: AR3 interacts with the s70 subunit of RNAP, affecting the rate of isomerization of RNAP-promoter closed complex to open complex. An example of a class II CAP-dependent promoter is the galP1 promoter, which controls the production of galactose-degrading enzymes from the gal operon.

Class III CAP-dependent promoter activation: two CAP dimers interacting with the aCTD of RNAP

Courtesy of Richard Ebright, Journal of Molecular Biology 293, S. Busby and R. Ebright, Transcription Activation by Catabolite Activator Protein (CAP), 199-213 (1999), PMID: 10550204

Transcription activation at class III CAP-dependent promoters involves the synergistic action of two or more CAP dimers at different DNA sites. Transcription activation at these promoters involve class I and class II mechanisms of action in an additive manner: the CAP dimers can both act through a class I mechanism, where the AR1 region of each CAP dimer interacts with each of the two RNAP aCTDs (as diagrammed above); alternatively, the two CAP dimers could function differently, with the upstream CAP dimer utilising a class I mechanism (AR1 interacting with one copy of RNAP aCTD), and the downstream CAP dimer utilising a class II mechanism (AR1 and AR2 interacting with RNAP aCTD and aNTD, respectively). Transcription at class III promoters can also involve the synergistic actions of CAP with other activator proteins, where the different activator proteins take the role of the second CAP protein in the mechanisms described above. As CAP does not directly interact with the other activator proteins, CAP is able to collaborate with a diverse array of unrelated activators that affect different steps in transcription initiation. An example of a class III CAP-dependent promoter is the malK promoter, which controls the production of a set of proteins involved in the absorption of maltose, maltodextrins and starch.

CAP repression

CAP transcription activation can be blocked by a number of different protein repressors. The CytR protein can inhibit CAP action at the deoP2, udp, nupG, and cdd promoters in the absence of the allosteric effector cytidine. CytR can interact with the DNA between two CAP dimers and with the CAP proteins themselves to prevent CAP-RNAP interaction, thereby completely blocking CAP-enhanced transcription. Alternatively, repressors such as bacteriophage Alt and ModA can block CAP-dependent transcription by binding to RNAP aCTD and preventing its interaction with DNA.

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