Expanding the Biological Importance of Protein Structures: Insight into Dynamic Biological Function from Protein...

While recent developments in the determination of the three-dimensional structure of proteins have rapidly progressed, there remains a difficult challenge of studying proteins that exhibit dynamic behavior as part of their biological functions in environments considerably different than how their three-dimensional structure was determined. This study investigates the dynamic behavior of Bax, a member of the Bcl-2 family of proteins, during the regulation of apoptosis in the context of its published three-dimensional structure. The location of Bax in live cells is an equilibrium between the cytosol and outer-mitochondrial membrane. However, the regions of Bax that have been determined to be responsible for this equilibrium are shown to be inaccessible to engage in these interactions, namely, the C-terminal helix, according to the solved three-dimensional structure. Therefore, the analyses that have been applied to identify chain folding initiation sites (CFIS) and propose unfolding pathways have also been applied to the three-dimensional structure of Bax to provide a rationale for how Bax can engage in the dynamic behavior that is part of its biological function. The analyses identified regions in Bax that contribute to its stability and regions that could be susceptible to conformational changes, including the C-terminal helix, and, consequently, dynamic behavior. Experimental observations confirmed the classification of these regions. Consequently, the utilization of methods to identify CFIS on three-dimensional structures can be an effective tool to help expand our knowledge about the biological function of proteins that exhibit dynamic behavior.