Generation of Peptide Agonists for Functional Mapping

Baylor College Of Medicine, Houston TX

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Abstract

Although most nuclear receptors are capable of binding to specific DNA response elements in the absence of other proteins, their ability to efficiently regulate target genes is dependent in large part upon their ability to recruit co-regulator proteins, including co-activators and co- repressors. Recruitment of co-regulators is known to depend on cell type, target gene and ligand, and a single nuclear receptor may recruit different sets of co-activators for a variety of functions. Since recruitment of these factors is required for many aspects of nuclear receptor function, we hypothesize that peptides capable of blocking the interaction with these factors will block one or more critical biological functions on nuclear receptors. Whereas major progress has been made in the last few years in identifying and characterizing co-regulators for liganded nuclear receptors, very little progress has been made in this respect for orphan nuclear receptors (ONRs). Therefore, the identification of peptides that interact with these receptors will great enhance our understanding of mechanistic aspects of ONR function. Furthermore, it has been shown that NR co-activators and co-repressors are themselves regulated by a variety of interactions which either occur within the context of large protein complexes of large protein complexes or with other co- regulators, and mutation of many of these interaction sites is known to abolish co-regulator activity. The identification of peptides that bind specifically to co-regulators in the vicinity of these interaction domains will therefore be extremely useful for elucidating the role of protein- protein interactions in the structure of co-regulator complexes and other mechanistic aspects of co-regulator function. In this bridging project, we will use phage display to identify, characterize and categorize peptides that interact with steroid receptor co-activators, (SRCs), co-repressors (SMRT and NCoR) and ONRs. The Specific Aims are: 1) To identify, characterize and categorize peptides that interact efficiently and specifically with ONRs and 2) To identify, characterize and categorize peptides that interact efficiently and specifically with the steroid receptor co-activators, SRC-1, SRC-2/GRIP-1/TIF2, SRC- 3/p/CIP/ACTR/RAC3/AIB1/TRAM-1 and the co-repressors.