Researchers from the University of North Carolina at Chapel Hill have identified a key molecular mechanism that may account for the development of cystic fibrosis.
The findings, published Feb. 29 in the open-access on-line journal PLoS Computational Biology, add new knowledge to understanding the development of this fatal disease and may also point the way to new corrective treatments.
Cystic fibrosis (CF) is the most common inherited chronic disease affecting the lung and digestive system. In the United States, about 1 in 3,000 children is born with cystic fibrosis. It is caused by a defective gene that produces a misshapen form of a protein called cystic fibrosis transmembrane conductance regulator (CFTR). People with cystic fibrosis do not have enough CFTR for their cells to work normally because their bodies quickly destroy the mutant protein.
About 90 percent of CF cases are due to the deletion of an amino acid building block in CFTR, in a major domain of the protein called NBD1. Earlier experimental studies have shown that the mutant NBD1 without the amino acid Phe508 has an increased tendency to misfold resulting in the premature degradation of CFTR.
Protein folding is the process in which protein molecules assume their intricate three-dimensional shape. In CF, the molecular basis of this increased misfolding tendency has remained elusive, said senior study author Nikolay Dokholyan, Ph.D., assistant professor of biochemistry and biophysics at UNC's School of Medicine.
“Understanding the molecular etiology of the disease is a key step to developing pharmaceutical strategies to fight this disease,” Dokholyan said.
Using sophisticated computer modeling techniques, the researchers performed extensive simulations of how normal and mutant NBD1 folded. Known as molecular dynamics simulations, these “virtual experiments” allowed researchers to view how atoms and molecules actually move according to known physical laws. When applied to the NBD1 protein, these simulations showed that the disease-causing mutant exhibits a higher misfolding tendency.
More importantly, by comparing the structures of the normal and the mutant NBD1 domains as they fold, the authors were able to determine critical pairs of amino acid residues that must come together for NBD1 to fold correctly. These interactions are modulators of CFTR folding, and hence, they are potential modulators of CF.
“Computer simulations approximate our understanding of natural phenomena. That our simulations correlated with known experimental studies is remarkable,” Dokholyan said. “More importantly, the molecular details of aberrant NBD1 folding provides guidance for the design of small molecule drugs to correct the most prevalent and pathogenic mutation in CFTR.”
The first author of the study is Adrian Serohijos, a graduate student in both the UNC School of Medicine's molecular and cellular biophysics program, and in the UNC College of Arts and Sciences' physics and astronomy department. Other co-authors include John Riordan, Ph.D., co-discoverer of the CFTR gene and professor of biochemistry and biophysics in the UNC School of Medicine; and postdoctoral research associate Tamas Hegedus, Ph.D., of the UNC Cystic Fibrosis Research Center.
The study was supported in part by grants from the Cystic Fibrosis Foundation, the National Institutes of Health, and the American Heart Association.
The paper can be found at http://www.ploscompbiol.org/doi/pcbi.1000008.