Description:

Protein folding in the cell relies heavily on chaperones. Even though much has been learned about chaperones, particularly in regard to their co-chaperone and co-factor requirements, observing how chaperones bind to a wide range of substrate proteins and affect their folding has proven to be very difficult. This difficulty primarily comes from two sources: the functional complexity of chaperone machines, and the fact that chaperone substrates are almost always poorly defined mixtures of partially structured folding intermediates. We decided to embark on a chaperone discovery journey with the aim of finding chaperones that are simpler and more biophysically tractable than those currently studied. Ideally, these new chaperones should act on a substrate protein whose folding mechanism is already well characterized, so that we can
determine precisely how the chaperone is affecting the folding of the substrate. We thus developed genetic selections that directly link the stability of model folding proteins to increased antibiotic resistance in vivo. The folding biosensors that we have developed function in the bacterial periplasm and cytosol, and in yeast. These biosensors have allowed us to optimize protein folding and discover new chaperones we used the first of our discovered chaperones, Spy, as a model to delve deeply into chaperone biology and we now understand, in unprecedented detail, how this chaperone interacts with client proteins to facilitate their folding. We are following our chaperone discovery efforts into yeast with the aim of addressing the role that host factors play in amyloid formation, which is linked to a number of devastating
neurological diseases.

James C. Bardwell, PhD
Rowena G. Matthews Collegiate Professor, Department of Molecular, Cellular, and Developmental Biology
Professor, Department of Biological Chemistry
University of Michigan
Howard Hughes Medical Institute Investigator