title: Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators.
abstract: Nuclear hormone receptors are ligand-activated transcription factors that regulate the expression of genes that are essential for development, reproduction and homeostasis. The hormone response is mediated through recruitment of p160 receptor coactivators and the general transcriptional coactivator CBP/p300, which function synergistically to activate transcription. These coactivators exhibit intrinsic histone acetyltransferase activity, function in the remodelling of chromatin, and facilitate the recruitment of RNA polymerase II and the basal transcription machinery. The activities of the p160 coactivators are dependent on CBP. Both coactivators are essential for proper cell-cycle control, differentiation and apoptosis, and are implicated in cancer and other diseases. To elucidate the molecular basis of assembling the multiprotein activation complex, we undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors. Here we show that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. Our study uncovers a unique mechanism, called 'synergistic folding', through which p160 coactivators recruit CBP/p300 to allow transmission of the hormonal signal to the transcriptional machinery.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Demarest
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Yamout
authors.forename: John
authors.initials: J
authors.lastname: Chung
authors.forename: Hongwu
authors.initials: H
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: H Jane
authors.initials: HJ
authors.lastname: Dyson
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Peter E
authors.initials: PE
authors.lastname: Wright
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C110421:Mybbp1a protein, mouse; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse