Structural and functional insights on the roles of molecular chaperones in the mistargeting and aggregation...

To carry out their biological function in cells, proteins must be folded and targeted to the appropriate subcellular location. These processes are controlled by a vast collection of interacting proteins collectively known as the protein homeostasis network, in which molecular chaperones play a prominent role. Protein homeostasis can be impaired by inherited mutations leading to genetic diseases. In this chapter, we focus on a particular disease, primary hyperoxaluria type 1 (PH1), in which disease-associated mutations exacerbate protein aggregation in the cell and mistarget the peroxisomal alanine:glyoxylate aminotransferase (AGT) protein to mitochondria, in part due to native state destabilization and enhanced interaction with Hsp60, 70 and 90 chaperone systems. After a general introduction of molecular chaperones and PH1, we review our current knowledge on the structural and energetic features of PH1-causing mutants that lead to these particular pathogenic mechanisms. From this perspective, and in the context of the key role of molecular chaperones in PH1 pathogenesis, we present and discuss current and future perspectives for pharmacological treatments for this disease.