Stewart Loh, PhD
RESEARCH PROGRAMS AND AFFILIATIONS
Protein engineering, design, and folding
The Loh lab applies biophysical, biochemical, structural, and cell-based approaches to carry out two research programs. The first program is to develop protein engineering strategies by which ordinary proteins can be converted to molecular switches. These technologies describe how to combine one protein (the input domain) with a second protein (the output domain) such that binding of a target ligand to the input domain causes the output domain to change its conformation and thus its biological activity. Our designs emphasize modularity—the ability to mix and match input and output domains for specific functionalities—and we have introduced multiple mechanisms for doing so (mutually exclusive folding, induced domain swapping, protein fragment exchange, and alternate frame folding). These switches are used as biosensors and for functional regulation in the cell.
Our second research focus is to delineate the roles that binding of zinc and other metals play in protein folding and misfolding. We were the first to describe the unique relationship between zinc ligation and folding/misfolding of the p53 tumor suppressor, and to design synthetic metallochaperones that modulate this interaction to restore function to mutant p53. More recently, we have established that loss of bound zinc triggers amyloid formation of the LECT2 protein, resulting in a common form of systemic amyloidosis that affects the kidney and liver. Developing therapies for restoring and maintaining proper zinc binding to proteins is a major focus of this program.