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Pharmacological chaperones: a new twist on receptor folding
J P Morello1, U E Petäjä-Repo, D G Bichet
1Department of Biochemistry, Université de Montréal, PO Box 6128, Downtown station, QC, H3C 3J7, Montreal, Canada. ere.umontreal.ca
Abstract:
Protein misfolding is at the root of several genetic human diseases. These diseases do not stem from mutations within the active domain of the proteins, but from mutations that disrupt their three-dimensional conformation, which leads to their intracellular retention by the quality control apparatus of the cell. Facilitating the escape of the mutant proteins from the quality control system by lowering the temperature of the cells or by adding chemicals that assist folding (chemical chaperones) can result in proteins that are fully functional despite their mutation. The discovery that ligands with pharmacological selectivity (pharmacological chaperones) can rescue the proper targeting and function of misfolded proteins, including receptors, might help to develop new treatments for 'conformational diseases'.
Insights
Genetic diseases stem from protein misfolding, not active site mutations. Pharmacological chaperones can rescue misfolded proteins, offering new treatments for conformational diseases.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Protein misfolding underlies many genetic human diseases.
- Mutations causing misfolding disrupt protein 3D structure, leading to cellular retention.
- Cellular quality control systems trap misfolded proteins, preventing function.
Purpose of the Study:
- To explore therapeutic strategies for genetic diseases caused by protein misfolding.
- To investigate the potential of pharmacological chaperones in treating conformational diseases.
Main Methods:
- Investigating the effects of temperature reduction on protein folding and function.
- Utilizing chemical chaperones to assist protein folding.
- Examining the impact of pharmacologically selective ligands (pharmacological chaperones) on misfolded proteins.
Main Results:
- Lowering cellular temperature can facilitate the escape of mutant proteins from quality control.
- Chemical chaperones can aid in achieving functional protein conformations.
- Pharmacological chaperones demonstrate potential in rescuing the targeting and function of misfolded proteins, including receptors.
Conclusions:
- Pharmacological chaperones represent a promising therapeutic approach for conformational diseases.
- Targeting protein misfolding and cellular quality control offers a route to treating genetic disorders.