Drs. John Orban and Philip Bryan Together Designed and Developed a System that Examines Mutational Requirements for Transitioning Between Folds and Functions

The laboratories of Drs. John Orban and Philip Bryan at the University of Maryland Institute of Bioscience and Biotechnology Research (IBBR) have worked together to design and develop a system that examines the mutational requirements for transitioning between folds and functions. The group published the findings in the February 8 issue of the Cell Press journal Structure, authored by He et al., titled “Mutational Tipping Points for Switching Protein Folds and Functions”. In this paper, the Orban and Bryan groups describe their recent research indicating that two different fold topologies can be flipped using single amino acid substitutions, and that these changes can occur in multiple ways. They also observed that a new function can be gained before the relevant fold is significantly populated. These data illustrate that changes in fold and function may not always coincide. The publication was also previewed in Structure, describing the work as providing the basis to “illuminate multiple pathways by which evolutionary fold switching might occur...” (Cordes MHJ and Stewart KL (2012) Structure 20, 199-200).

The work described by Drs. Orban and Bryan has relevance to understanding how new protein folds and functions evolve - it also provides conceptual challenges for understanding how amino acid sequence determines three-dimensional structure. As such, this work has triggered significant interest from the computational structure prediction community. While the ability of proteins to switch folds is currently considered uncommon and relatively few have been characterized structurally, there are well known ‘‘metamorphic’’ proteins that can adopt more than one folded state. Often, fold changes are initiated by environmental factors such as salt conditions, the presence of a ligand, and redox state. Known examples of metamorphic proteins are prions, polypeptides that undergo conformational changes to convert from a benign protein to an infectious one. The number of described metamorphic proteins is growing, suggesting that fold switching may occur more often than previously appreciated. One possible reason why there are not more reports is that the sequences of many such proteins may be transient and rapidly transition to their new functions and folds.

Dr. John Orban, who is also a Professor in the Department of Chemistry and Biochemistry at the University of Maryland, is a recognized expert in applying high field NMR spectroscopic methods to determine novel protein structures and to better understand the complex relationship between protein sequence and structure. Dr. Philip Bryan, who is also a Professor in the Department of Bioengineering at the University of Maryland, is recognized as an expert in proteases and designing functional protein switches. The efforts in Dr. Bryan's group include using genetic, biochemical and biophysical methods to study complex questions on protein folding.