Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Evolution of Structure and Dynamics for a Family of Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) perform essential functions in organisms from all phyla. IDPs do not form tertiary structures and contain varying amounts of secondary structure. In order to develop general relationships between the structure and function of IDPs, we are investigating the structure and dynamics of protein families that are intrinsically disordered. The work is being placed in an evolutionary context to permit the identification of important structural features by virtue of their conservation and constitutes the first attempt to quantify the relationship between sequence identity and structural similarity for IDPs. The intrinsically disordered transactivation domain of the tumor suppressor, p53 (p53TAD) is one model system chosen for study. Significant differences are observed in the secondary structure and dynamics of mammalian homologues of p53TAD. These differences are primarily localized to the binding sites for the ubiquitin ligase, MDM2 and the 70 KDa subunit of replication protein A (RPA70) and appear to influence the kinetics and thermodynamics of binding. We are also investigating the role of prolines in controlling the structure and dynamics of IDPs. Mutating the conserved prolines that flank the MDM2 binding site has a striking effect on the structure and dynamics of this region. An analysis of other IDPs that fold when they bind to their protein partners shows that proline residues are enriched in the regions flanking the binding sites, suggesting the structural and dynamical effects observed for the p53TAD homologues are general.

This work is supported by the American Cancer Society (RSG-07-289-01-GMC) and the National Science Foundation (MCB-0939014)

1Gary W. Daughdrill
1Wade Borcherds
1Hongwei Wu
2Bin Xue
2Vladimir Uversky

1Department of Cell Biology, Microbiology, and Molecular Biology and Center for Drug Discovery and Innovation
2Department of Molecular Medicine University of South Florida Tampa Fl, 33612

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