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Molecular and Cellular Biology, August 1999, p. 5601-5607, Vol. 19, No. 8
Joslin Diabetes Center, Research Division,
Department of Cell Biology, Harvard Medical School, Boston,
Massachusetts 021381; Department of
Molecular Biology, The Skaggs Institute for Chemical Biology, The
Scripps Research Institute, La Jolla, California
920373; and Department of
Biochemistry2 and Department of
Experimental Oncology,4 St. Jude Children's
Research Hospital, Memphis, Tennessee 38105
Received 11 March 1999/Returned for modification 28 April
1999/Accepted 24 May 1999
We have examined structural differences between the proto-oncogene
c-Myb and the cyclic AMP-responsive factor CREB that underlie their
constitutive or signal-dependent activation properties. Both proteins
stimulate gene expression via activating regions that articulate with a
shallow hydrophobic groove in the KIX domain of the coactivator
CREB-binding protein (CBP). Three hydrophobic residues in c-Myb that
are conserved in CREB function importantly in cellular gene activation
and in complex formation with KIX. These hydrophobic residues are
assembled on one face of an amphipathic helix in both proteins, and
mutations that disrupt c-Myb or CREB helicity in this region block
interaction of either factor with KIX. Binding of the helical c-Myb
domain to KIX is accompanied by a substantial increase in entropy
that compensates for the comparatively low enthalpy of complex
formation. By contrast, binding of CREB to KIX entails a large entropy
cost due to a random coil-to-helix transition in CREB that accompanies
complex formation. These results indicate that the constitutive and
inducible activation properties of c-Myb and CREB reflect secondary
structural characteristics of their corresponding activating regions
that influence the thermodynamics of formation of a complex with CBP.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Role of Secondary Structure in Discrimination
between Constitutive and Inducible Activators
*
Corresponding author. Present address: Salk Institute,
10010 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 453-4100. Fax: (619) 552-1546.
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