Book of Abstracts: Albany 2009

category image Albany 2009
Conversation 16
June 16-20 2009
© Adenine Press (2008)

Analysis of the Role of Intrinsic Disorder in Multiple Specificity

Several lines of evidence suggest that intrinsically disordered proteins (IDPs) are a common mechanism used by nature to mediate protein-protein interactions. It is thought that IDPs can facilitate protein interactions through an ability to mediate binding diversity, where one of the proposed mechanisms for this is multiple specificity ? i.e. recognition of multiple molecular partners through use of the same binding residues ? through contextual folding of IDPs. We are examining the role of IDPs and protein flexibility in multiple specificity. In previous work, three contrasting examples of protein regions with multiple binding specificity were examined: 14-3-3ζ, p53 C-terminal regulatory domain, and p53 DNA binding domain (DBD). The 14-3-3ζ and p53 C-terminal domains exemplify the potential of intrinsic disorder for mediating protein interactions. The 14-3-3ζ domain is structured with a single binging pocket that is responsible for the binding of various protein partners through interaction with sequence divergent, intrinsically disordered segments in these partners. In contrast, the intrinsically disordered C-terminus of p53 contains a discrete regions that is involved in many interactions with different protein partners (Figure 1), where these interactions regulate p53 function. The common theme in both of these examples is structural variability in the bound state that is enabled by intrinsic disorder in one of the partners in the unbound state. The final example, the p53 DBD, is a folded domain and the experimental structures of it complexed with four distinct, ordered partners have been determined. Our analysis of these structures indicates that flexibility in the DBD is an important element in the DBD's ability to bind multiple partners. In current work, the previous analysis is expanded to many other examples of proteins that interact with multiple partners using a common binding site. Both the ordered and disordered regions of these structures are examined and these data are interpreted in terms of the role of intrinsic disorder and flexibility in multiple specificity.

Christopher J. Oldfield1
Vladimir N. Uversky1,2
A. Keith Dunker1

1Ctr for Computational Biology
and Bioinformatics
Indiana Univ Schools of
Medicine and Informatics
410 W. 10th Street
Indianapolis, IN 46202, USA
2Inst. for Biological Instrumentation
Russian Academy of Sciences
142290 Pushchino
Moscow Region, Russia


Figure 1: Comparison of the experimentally determined structures of the same region of the C-terminus of p53