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Molecular and Cellular Biology, October 2005, p. 8792-8808, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.8792-8808.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of the Amino-Terminal Transcription Activation Domain of Progesterone Receptor by a Cofactor-Induced Protein Folding Mechanism

Suzanne E. Wardell,1,{dagger} Stanley C. Kwok,3 Lori Sherman,2 Robert S. Hodges,3 and Dean P. Edwards1,2*

Molecular Biology Program, University of Colorado Health Sciences Center, Aurora, Colorado,1 Pathology, University of Colorado Health Sciences Center, Aurora, Colorado,2 Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, Colorado3

Received 29 November 2004/ Returned for modification 14 January 2005/ Accepted 14 July 2005

We previously identified a small basic leucine zipper (bZIP) protein, Jun dimerization protein 2 (JDP-2), that acts as a coregulator of the N-terminal transcriptional activation domain of progesterone receptor (PR). We show here that JDP-2, through interaction with the DNA binding domain (DBD), induces or stabilizes structure in the N-terminal domain in a manner that correlates with JDP-2 stimulation of transcriptional activity. Circular dichroism spectroscopy experiments showed that JDP-2 interaction caused a significant increase in overall helical content of a two-domain PR polypeptide containing the N-terminal domain and DBD and that the change in structure resides primarily in the N-terminal domain. Thermal melt curves showed that the JDP-2/PR complex is significantly more stable than either protein alone, and partial proteolysis confirmed that JDP-2 interaction alters conformation of the N-terminal domain of PR. Functional analysis of N-terminal domain mutants and receptor chimeras provides evidence that the stimulatory effect of JDP-2 on transcriptional activity of PR is mediated through an interdomain communication between the DBD and the N-terminal domain and that transcriptional activity and functional response to JDP-2 are mediated by multiple elements of the N-terminal domain as opposed to a discrete region.

* Corresponding author. Present address: Dept. of Mol. Cell. Biol., Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM-130, Houston, TX 77030. Phone: (713) 798-2326. Fax: (713) 790-0545 E-mail: deane{at}bcm.tmc.edu.

{dagger} Present address: Duke University Medical Center Pharmacology and Cancer Biology, Box 3813, Durham, NC 27710.

Molecular and Cellular Biology, October 2005, p. 8792-8808, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.8792-8808.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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