|Protein Intrinsic Disorder, Cell Signaling, Drug Discovery, and Alternative Splicing
Professor A. K. Dunker
Founder/Father of Protein Trinity and Intrinsic Disorder
Director of Computational Biology and Bioinformatics
Indiana University Purdue University
Indianapolis and Bloomington, Indiana, USA
Date: June 26, 2007
Time: 3:20 - 4:20 PM
Location: Ballroom 5
Many proteins, including at least 2/3 of the protein structures in the Protein Data Bank, contain regions that lack specific 3-D structure; indeed some proteins lack specific 3-D structure in their entireties under physiological conditions and yet carry out function as indicated by appropriate biochemical assays. Such proteins and regions have been called natively unfolded, intrinsically unstructured, naturally disordered, and rheomorphic, and various combinations of these terms among others. Starting in 1996, we began to explore the prediction of structured and disordered regions from amino acid sequence. This is distinct from the prediction of irregular (also called random coil) regions. Disorder predictions by us and others suggest that a large fraction of eukaryotic proteins contain significant-sized regions of disorder. Intrinsic disorder is found to be commonly used in cell signaling, for example for protein-protein and protein-DNA interaction networks. Disorder-to-order-transitions upon binding have at least two advantages:
1- The ability to bind with high specificity coupled with weak affinity due to the flexibility in the unbound state.
2- The ability to bind to two or more partners due to plasticity in the bound state.
Recently eight small molecules are promising new drugs due to their interference with protein-protein interactions. In four of the eight examples, one of the protein is structured and the other is disordered, with the small molecule binding to the structured protein and thereby blocking its interaction with the disordered partner. This provides a new approach to drug discovery. Alternative splicing is very common in multicellular eukaryotes but rare or perhaps non-existent in single-cell eukaryotes. The RNA removed by alternative splicing is found to code for regions of intrinsic disorder significantly more often than for regions of structure. Given that signaling segments in regions of disorder are formed from small numbers of contiguous amino acids, and given that many disordered regions have been shown to contain many signaling and regulatory segments in tandem, alternative splicing within regions of disorder provides a simple method for bringing about regulatory and signaling diversity. We propose that the combination of alternative splicing plus intrinsic disorder provided a means to "try out" alternative regulatory pathways, thus enabling the evolution of differentiated cells.
Dr. A. Keith Dunker received a broad education, with degrees in chemistry (UC Berkeley, 1965), physics (UW Madison, 1967), and biophysics (UW Madison, 1969), and with postdoctoral training in structural biology (1969-1973, Yale University). After spending a career using biophysics and spectroscopy to study virus and phage structure and assembly as models for understanding connections between protein conformational changes and function, in the middle 1980s Dr. Dunker realized the coming importance of computational biology and bioinformatics and began to teach, to work and especially to collaborate "on the side" in these newly developing areas. His biophysics work and his computational hobby merged in the mid 1990s with the realization that many proteins lacked 3D structure yet carried out function and could be studied as a group using bioinformatics approaches and methods. His "second career," which focuses on the bioinformatics of intrinsically disordered proteins, is leading to novel ideas regarding protein structure and function, and these will be the topics of his seminar. He is highly regarded in the field as Founder/Father of The Protein Trinity and Intrinsic Disorder concepts, and his work has contributed significantly to increased understanding of the importance of protein disorder. Dr. Dunker's research is supported by NIH and by the Indiana Genomics Initiative, funded in part by the Lilly Endowment. He is currently T. K. Li Distinguished Professor of Medical Research and Director of the Center for Computational Biology and Bioinformatics of Indiana University. The Endowed Professorship title, T. K. Li, honors the current general director of the NIH/NIAAA.