FIGURE 9-31 Activation domains may be random coils until they interact with co-activator proteins or folded protein domains. (a) The acidic activation domain of CREB (cyclic AMP response element-binding protein) is activated by phosphorylation at serine 123. It is a random coil until it interacts with a domain of its co-activator, CBP (shown as a space-filling surface model with negatively charged regions in red and positively charged regions in blue). When the CREB activation domain binds to CBP, it folds into two amphipathic α helices. Side chains in the activation domain that interact with the surface of the CBP domain are labeled. (b) The ligand-binding activation domain of the estrogen receptor is a folded-protein domain. When estrogen is bound to the domain, the green α helix interacts with the ligand, generating a hydrophobic groove in the ligand-binding domain (dark brown helices), which binds an amphipathic α helix in a co-activator subunit (blue). (c) The conformation of the estrogen receptor in the absence of hormone is stabilized by binding of the estrogen antagonist tamoxifen. In this conformation, the green helix of the receptor folds into a conformation that interacts with the co-activator–binding groove of the active receptor, sterically blocking binding of co-activators.

[Part (a) data from I. Radhakrishnan et al., 1997, Cell 91:741, PDB ID 1kdx. Parts (b) and (c) data from A. K. Shiau et al., 1998, Cell 95:927, PDB ID 3erd and 3ert.]