Nuclear Receptors (NRs) are a large family of transcription factors that control a broad range of biological processes. Although the activity of many NRs is regulated by ligand, a large number of these receptors are orphan NRs that share a common fold with NRs with known ligands. This likely reflects the ancestral state of this protein family. How is the activity of orphan NRs regulated? Drosophila Ftz-F1 is the founding member of the NR5A nuclear receptor family. In previous work, we showed that Drosophila αFtz-F1 interacts with the homeodomain protein Ftz, a classic pair-rule protein expressed in seven stripes in embryos in the primordia of body regions missing in ftz mutant animals. Ftz-F1 and Ftz form a stable complex in vivo and bind to composite DNA sites, synergistically activating target gene expression. Thus, although Ftz-F1 is a strong transcriptional activator alone in vitro, and it is present in the nuclei of all somatic cells of the embryo, its activity is limited to the cells in which Ftz is also expressed (Ftz+ cells). These studies demonstrate that protein-protein interactions modulate Ftz-F1 activity and provide an in vivo model system to dissect the mechanisms underlying this regulation. Here we will test whether Ftz-F1 is regulated (1) at the level of DNA binding, (2) by acorepressor/coactivator exchange, (3) by Ftz-induced conformational change and/or (4) by post-translational protein modifications. We will combine biochemical and structural methods with molecular genetic approaches in Drosophila embryos to evaluate the contributions of each of these mechanisms to the regulation of NR activity in vivo.
|Effective start/end date||8/15/15 → 6/30/18|
- University of Maryland, College Park (Z4573001//IOS-1457145)
- National Science Foundation (Z4573001//IOS-1457145)
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