Grant: Project Grant

The lysosome is a compartment in the cell that acts as the waste disposal system. It degrades proteins, fats, carbohydrates and other molecules so that their components parts can be reused. This is accomplished by numerous enzymes in the lysosome that break up the unwanted molecules. The task of directing these enzymes into the lysosome is a critical step that is currently not well understood at the molecular level. It involves the recognition of numerous unrelated enzymes by a series of protein complexes in the endoplasmic reticulum that tags the enzymes with a marker called M6P. This marker guides the enzymes to the lysosome. This proposal is aimed at understand the molecular basis for the process of marking lysosomal enzymes using structure imaging techniques. Specifically, we are interested in how the protein complex called GNPT manages to mark lysosomal destined enzymes with M6P. Deficiency of GNPT prevents enzymes from reaching the lysosome in many cell types and organs, and mutations in the GNPT gene cause several severe lysosomal storage diseases, for which there are no cures. The results from this proposal will help understand how this process works in great detail, which will be important for designing strategies to help treat diseases.