title: A progesterone receptor co-activator (JDP2) mediates activity through interaction with residues in the carboxyl-terminal extension of the DNA binding domain.
abstract: Progesterone receptor (PR) belongs to the nuclear receptor family of ligand-dependent transcription factors and mediates the major biological effects of progesterone. Transcriptional co-activators that are recruited by PR through the carboxyl-terminal ligand binding domain have been studied extensively. Much less is known about co-activators that interact with other regions of receptors. Jun dimerization protein 2 (JDP2) is a PR co-activator that enhances the transcriptional activity of the amino-terminal domain by increasing the alpha-helical content and stability of the intrinsically disordered amino-terminal domain. To gain insights into the mechanism of JDP2 co-activation of PR, the structural basis of JDP2-PR interaction was analyzed using NMR. The smallest regions of each protein needed for efficient protein interaction were used for NMR and included the basic region plus leucine zipper (bZIP) domain of JDP2 and the core zinc modules of the PR DNA binding domain plus the intrinsically disordered carboxyl-terminal extension (CTE) of the DNA binding domain. Chemical shift changes in PR upon titration with JDP2 revealed that most of the residues involved in binding of JDP2 reside within the CTE. The importance of the CTE for binding JDP2 was confirmed by peptide competition and mutational analyses. Point mutations within CTE sites identified by NMR and a CTE domain swapping experiment also confirmed the functional importance of JDP2 interaction with the CTE for enhancement of PR transcriptional activity. These studies provide insights into the role and functional importance of the CTE for co-activator interactions.
authors: Molecular Biology Program, School of Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors: Krista K
authors: KK
authors: Hill
authors: Sarah C
authors: SC
authors: Roemer
authors: David N M
authors: DN
authors: Jones
authors: Mair E A
authors: ME
authors: Churchill
authors: Dean P
authors: DP
authors: Edwards
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D016350:Leucine Zippers; D019906:Nuclear Magnetic Resonance, Biomolecular; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary / Q000502:physiology; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism
chemical_list: C491387:JDP2 protein, human; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D015534:Trans-Activators