Integrated Calendar

Assaf friedler, Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel

Our group is interested in using peptides for the quantitative biophysical and structural analysis of protein-protein interactions in health and disease. Based on this, we develop lead compounds that modulate PPI for therapeutic purposes. One such promising way for manipulating protein function is the "shiftides" approach, by which we use peptides to modulate the oligomeric state of proteins1.
About one third of the genome encodes for intrinsically disordered proteins (IDPs) or regions in proteins. These lack stable tertiary structures and are extended, highly flexible, and composed of a large ensemble of conformations interchanging dynamically. Molecular recognition and assembly of IDRs typically involve multiple binding partners, which may result in disorder-to-order transitions. Various IDPs are involved in human diseases, making them attractive targets for drug design. Our research focuses on how intrinsic protein disorder regulates protein activity and how intrinsically disordered regions (IDRs) in proteins can be set as therapeutic targets. In many cases the C-terminal tail of a disease-related protein is disordered and has an important role in regulation. This sets disordered protein tails as particularly interesting drug targets. I will describe our studies regarding several IDRs in proteins involved in cancer and apoptosis:
1. Studying how the disordered C-terminal tailpiece of non-muscle myosin II regulates its activity by regulating its filament assembly2
2. How the disordered C-terminal domain of the pro-apoptotic ARTS protein regulates its activity by binding the target protein XIAP3
3. Developing peptides that bind the disordered C-terminal domain of the tumor suppressor p53 and stabilize the p53 tetramer4


References:
1 Hayouka, Z. et al. Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc Natl Acad Sci U S A 104, 8316-8321, (2007).
2 Ronen, D. et al. The positively charged region of the myosin IIC non-helical tailpiece promotes filament assembly. The Journal of biological chemistry 285, 7079-7086, (2010).
3 Reingewertz, T. H. et al. Mechanism of the Interaction between the Intrinsically Disordered C-Terminus of the Pro-Apoptotic ARTS Protein and the Bir3 Domain of XIAP. PLoS One 6, e24655, (2011).
4. Gabizon, R, et al. Modulating the Oligomerization Equilibrium of p53 by Peptides that Bind its C-Terminal Domain, Submitted for publication (2011)