Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Poster Session I

8-POS Board 8 Investigating the Structural Basis for Recruitment of CBP/p300 by E2A David N. Langelaan , Alyssa K. Kirlin, Marina Lochead, Seth Chitayat, Steven P. Smith. Queen's University, Kingston, Canada. E2A is a transcription factor that is essential for proper regulation of B-lymphocyte development and disruption of E2A through a t(1;19) chromosomal translocation is associated with acute lymphoblastic leukemia. The product of the t(1;19) translocation is the oncoprotein E2A-PBX1 which contains the unstructured activation domains (AD) of E2A and most of the PBX1 protein, including the DNA binding domain. Previous work from our group has determined that leukemogenesis primarily requires AD1 of E2A and the KIX domain from CBP/p300. However, the activation domains of E2A are able to recruit CBP/p300 in a cooperative manner, suggesting that other modules of CBP/p300 may be involved in forming the E2A:CBP complex. The objective of this study was to isolate other domains of CBP/300 which recognize E2A. Using complementary biophysical techniques such as peptide microarrays, isothermal titration calorimetry, pull-down experiments and nuclear magnetic resonance spectroscopy we have determined that AD1 of E2A adopts a helical structure when it binds to the Taz2 domain of CPB/p300. These results illustrate how the unstructured activation domains of E2A are able to recognize multiple domains of CBP/p300, allowing for cooperative recruitment of CBP/p300 by E2A. 9-POS Board 9 CD and NMR Conformational Preferences of Intrinsically Disordered Amphiphilic Peptides: A New Class of Potential Targets in Drug Discovery Diego Tesauro 1,2 , Marian Vincenzi 1 , Flavia A. Mercurio 2 , Antonella Accardo 1,2 , Luisa Ronga 3 , Marilisa Leone 2 , Filomena Rossi 1,2 . 1 University of Naples "Federico II", Naples, Italy, 2 CNR, Naples, Italy, 3 University of Bordeaux, Bordeaux, France. Owing to the large panel of biological functions of peptides and their high specificity and potency, the development of peptide-based therapeutic and diagnostic tools has received increased interest. Peptide amphiphiles (PAs) are an emerging class of molecules in which a bioactive peptide is covalently conjugate to a hydrophobic moiety1. Due to the coexistence in the molecule of a hydrophilic peptide sequence and a hydrophobic group, PAs are able to self- assemble spontaneously into a variety of nanostructures, such as monolayers, bilayers, and vesicles. In this work we have synthesized predicted by MEDOR2 disordered peptide sequences3 functionalized by alkyl chains, and connected by ethoxylic-based linker. The structural properties in solution of these new PAs were investigated using CD, NMR and DLS. The presence of the alkyl chains induces not only the self-assembly of these new PAs into supramolecular aggregates but also a gain of structure within the disordered peptide. The design of supramolecular systems, generated by joining a disordered peptide and a lipophilic moiety, could drive the disordered peptide to fold into a stable structure. This structural modification could be a promising route to develop a new class of bio-molecules for processes in which a specific conformational rearrangement is required.

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