The goal of our laboratory is to understand the molecular mechanisms by which the cell mediates protein folding and secretion. Despite decades of effort, the protein-folding problem remains one of the most challenging questions in molecular biology. In addition, protein folding inside the cell often faces difficulty, leading to misfolding and aggregation. To overcome these problems, cells have developed sophisticated mechanisms ranging from simple chaperoning, to active folding assistance, to the complex unfolded protein response (UPR). Protein folding problems have been directly linked to many disease states including cystic fibrosis, diabetes, various clotting disorders, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. We use protein crystallography to study the structures of proteins directly related to in vivo protein folding, secretion and the stress response.