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Strategies for correcting the delta F508 CFTR protein-folding defect
C R Brown1, L Q Hong-Brown, W J Welch
1Department of Medicine, The University of California, San Francisco 94143, USA.
Abstract:
Many human diseases arise as a result of mutations within genes encoding essential proteins. In many cases, the mutations are not so severe as to render the protein biologically inactive. Rather, the mutations oftentimes result in only subtle protein-folding abnormalities. In the case of the CFTR protein, a mutation leading to the loss of a single amino acid is responsible for the diseased state in the majority of individuals with cystic fibrosis. Here the newly synthesized mutant CFTR protein, missing a phenylalanine residue at position 508 (delta F508 CFTR), is unable to transit from the endoplasmic reticulum to the plasma membrane, where it functions as a regulator of chloride transport. All of the available evidence indicate that the newly synthesized delta F508 CFTR protein adopts a slightly altered conformation and therefore is retained at the level of the endoplasmic reticulum, ostensibly by the actions of the cellular quality control system. Because the mutant protein is capable of functioning as a chloride channel, developing ways to elicit its release out of the ER and to the plasma membrane has important clinical implications. Herein, we discuss our recent studies showing that the protein-folding defect associated with the delta F508 CFTR mutation, as well as a number of other temperature-sensitive mutations, can be overcome by strategies designed to influence protein folding inside the cell. Specifically we show that a number of low-molecular-weight compounds, all of which are known to stabilize proteins in their native conformation, are effective in rescuing the folding and/or processing defects associated with different mutations that oftentimes lead to human disease.
Insights
Small molecule compounds can correct protein misfolding in cystic fibrosis by helping the delta F508 CFTR protein reach the cell membrane, offering a potential therapeutic strategy for this genetic disease.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Many human diseases stem from mutations causing subtle protein-folding abnormalities, not complete inactivity.
- The delta F508 mutation in the CFTR protein is a primary cause of cystic fibrosis, leading to its retention in the endoplasmic reticulum.
- The misfolded delta F508 CFTR protein is retained in the ER due to cellular quality control mechanisms, despite retaining chloride channel function.
Purpose of the Study:
- To investigate strategies for rescuing the folding and processing defects of the delta F508 CFTR protein.
- To explore the potential of small molecules in correcting protein misfolding defects associated with genetic diseases.
Main Methods:
- Studied the delta F508 CFTR mutation and other temperature-sensitive mutations.
- Utilized low-molecular-weight compounds known to stabilize native protein conformations.
- Assessed the ability of compounds to rescue folding and processing defects in mutant proteins.
Main Results:
- Demonstrated that small molecules can overcome the protein-folding defect of delta F508 CFTR.
- Showed that these compounds can facilitate the release of mutant CFTR from the endoplasmic reticulum.
- Identified specific compounds effective in rescuing folding and processing defects in various disease-related mutations.
Conclusions:
- Small molecules can be leveraged to correct protein-folding defects, offering a promising therapeutic avenue for diseases like cystic fibrosis.
- Influencing intracellular protein folding with small molecules presents a viable strategy to restore function to misfolded proteins, such as delta F508 CFTR.