Rescuing Proteins of Low Kinetic Stability by Chaperones and Natural Ligands: Phenylketonuria, a Case Study

Phenylketonuria (PKU) is a disease caused by deleterious mutations in phenylalanine hydroxylase (PAH) and constitutes a paradigm for misfolding diseases. Folding is the process by which a protein reaches a functional and stable native structure, while misfolding can be seen as the failure to attain this fully functional conformation. Natural substrates, cofactors, and inhibitors have effects on protein stability beyond their functional role in enzyme function by the same arguments as for other specific ligands and can be considered as natural chaperone ligands. To avoid pathogenic misfolding, the cell is equipped with protein quality control systems (QCS) mainly including chaperones, the ubiquitin proteasome pathway (UPP) and, in some instances, the aggresome. Binding of a ligand to a specific binding site on the native state of a protein will influence the unfolding equilibrium which will be shifted towards the natively folded state, resulting in an increase in protein stability.