Book of Abstracts: Albany 2009

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

Hypothesis: Signaling Diversification Is Enabled by Alternative Splicing, Posttranslational Modification, and Multiple Partner Binding at Loci Within Intrinsically Disordered Protein Regions

As a cell divides with differentiation, diversified signaling networks necessarily develop within the two daughter cells. The common term that describes this process is gene regulation. The mechanisms by which gene regulation leads to signaling diversification remain unclear. Here we would like to propose a scenario that could possibly provide the mechanisms that underlie cell differentiation. First, we noticed that signaling proteins are abundant in regions that fail to form 3-D structure under physiological conditions but that rather remain as flexible ensembles. Intrinsically disordered is the term we use for such flexible regions of protein. Some signaling proteins are entirely disordered. Second, experiments indicate that such flexible, intrinsically disordered regions contain the sites for binding to protein or DNA or RNA partners. Third, these partner-binding sites often use their flexibility to adapt to multiple, differently shaped partners. Alternatively, sites within different disordered sequences can use their flexibility to adapt to a common binding site. By these mechanisms intrinsic disorder is very important in signaling networks and, for example, both transcription factors and hub proteins are highly enriched in disordered protein. Fourth, these flexible binding sites often contain residues that undergo posttranslational modification; evidently because the flexibility facilitates enzyme binding. Such posttranslational modifications are commonly observed to alter the binding specificity of the flexible site. Fifth, disordered regions often contain multiple binding sites in tandem, and both single binding sites and multiple sites in tandem are subject to modification via alternative splicing. The lack of structure in these regions facilitates alternative splicing, and indeed allows the possibility of multiple splicing events. Furthermore, the lack of structural constraints in disordered regions also facilitates the occurrence of point mutations. We are currently studying embryonic stem-cell associated developmental pathways to determine whether the coordinated combination of the features indicated above could provide an underlying mechanism for cell differentiation.

A. Keith Dunker

Center for Computational Biology and Bioinformatics
Indiana University School of Medicine
Indianapolis, Indiana 46202

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