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J Biol Chem, Vol. 275, Issue 20, 15014-15018, May 19, 2000
From the A 58-amino acid region mediates the core
transactivation activity of the glucocorticoid receptor
Architectural Principles for the Structure and Function of the
Glucocorticoid Receptor
1 Core Activation Domain*
§¶,, and§
Department of Biosciences, Karolinska
Institutet, Novum, Huddinge S-141 57, Sweden and
§ Södertörns Högskola, Box 4101, Huddinge S-141 04, Sweden
1 activation
domain. This 1 core domain is unstructured in aqueous buffers, but
in the presence of trifluoroethanol three 
-helical segments are
induced. Two of these putative structural modules have been tested in
different combinations with regard to transactivation potential
in vivo and binding capacity to the coactivators in
vitro. The results show that whereas single modules are not
transcriptionally active, any combination of two or three modules is
sufficient, with trimodular constructs having the highest activity.
However, proteins containing one, two, or three segments bind Ada2 and
cAMP-response element-binding protein with similar affinity. A single
segment is thus able to bind a target factor but cannot transactivate
target genes significantly. The results are consistent with models in
which activation domains are comprised of short activation modules that
allow multiple interactions with coactivators. Our results also suggest
that an increased number of modules may not result in correspondingly higher affinity but instead that the concentration of binding sites is
increased, which gives rise to a higher association rate. This is
consistent with a model where the association rate for activator-target
factor interactions rather than the equilibrium constant is the most
relevant measure of activator potency.
*
This work was supported by Swedish Natural Sciences Research
Council Grants KU9756 and LS9756 and Swedish Medical Research Council
Grant 13x-2819.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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