Regulation of DNA Binding by Autoinhibition Mechanism

Autoinhibition is a phenomenon that usually involves intramolecular interactions and provides a framework for regulation of protein function (Pufall and Graves 2002). For the last decade we have investigated an autoinhibitory mechanism that regulates the DNA binding of Ets-1 (Petersen et al. 1995). We have characterized a partnership with a second transcription factor, RUNX1, which counteracts this autoinhibition (Goetz et al., 2000). More recently, we have investigated a calcium-dependent signaling pathway that reinforces the autoinhibition (Cowley and Graves 2000). Structural and dynamic studies have led to a detailed mechanism for autoinhibition that illustrates the dynamic nature of proteins and how this property is used in regulation (Garvie et al. 2002; Lee et al. 2005; Pufall et al. 2005). Of particular significance is the finding that unstructured regions can do work and that multiple phosphates can work in a graded manner to regulation protein activity. Our investigations of Ets-1 autoinhibition include ongoing collaborations with structural biologists (e.g., Cynthia Wolberger, Johns Hopkins, Lawrence McIntosh, U. British Columbia, and Lewis Kay, University of Toronto).