Distinguished Lecture Series Guest Speaker:
Peter E. Wright
Professor and Chair
Cecil H. and Ida M. Green Investigator in Biomedical Research
Department of Molecular Biology
The Scripps Research Institute
Intrinsically disordered proteins participate in important regulatory functions in the cell, including regulation of transcription, translation, the cell cycle, and numerous signal transduction events. Disordered proteins often undergo coupled folding and binding transitions upon interaction with their cellular targets. The lack of stable globular structure can confer numerous functional advantages, including, paradoxically, both binding promiscuity and high specificity in target interactions. NMR is unique in being able to provide detailed insights into the intrinsic conformational preferences and dynamics of unfolded and partly folded proteins, and into the mechanism of coupled folding and binding. The function of intrinsically disordered protein domains in transcriptional regulation and signaling will be described, with particular reference to the general transcriptional coactivators CBP and p300, the tumor suppressor p53, and the adenovirus E1A oncoprotein. The globular domains of CBP/p300 are targets for coupled folding and binding of disordered transactivation motifs of numerous transcription factors and viral oncogenes, which compete for binding to limiting amounts of CBP/p300. Many intrinsically disordered proteins contain multipartite interaction motifs that perform an essential function in the integration of complex signaling networks. The role of multipartite binding motifs and post translational modifications in regulation of p53-mediated signaling pathways will be discussed.