Grant: Operating Grant

Proteins that reside on the surface of cells or that are secreted from cells are initially made in a compartment called the endoplasmic reticulum (ER). The ER provides an environment that helps proteins fold into their correct three-dimensional shape and it is also responsible for "quality control", a process in which proteins that do not fold correctly are retained and ultimately destroyed. Many human diseases, such as cystic fibrosis and juvenile emphysema, are caused by mutant proteins that do not fold correctly, leading to their retention and destruction in the ER. This is unfortunate because some of these mutant proteins could still function if the quality control system of the ER would release them and allow their movement to their correct cellular location. We are studying several groups of molecules of the human ER, including the molecular chaperones calnexin and calreticulin, more than 25 enzymes of the thiol oxidoreductase and peptidyl prolyl isomerase families, as well as "ERAD" molecules that are dedicated to the recognition and disposal of improperly folded proteins. Our current experiments are designed to modify or eliminate each of these molecules to determine their functions in protein folding and in quality control, and the extent of cooperation between them. We and others are finding that some of these molecules promote proper protein folding, others participate in quality control, and some are involved in both processes. Our goal is to obtain a thorough understanding of their functions and how their actions are coordinated so that we can design therapeutic strategies to improve the folding of disease-associated mutant proteins and to promote their exit from the ER.