Cystic Fibrosis Development Better Understood

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Main Category: Cystic Fibrosis
Also Included In: Genetics
Article Date: 10 Mar 2008 - 0:00 PDT

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According to a report in the open-access journal PLoS Computational Biology, there is a specific molecular mechanism that could be responsible for the development of cystic fibrosis. The University of North Carolina at Chapel Hill researchers suggest better understanding of the disease may help to develop new corrective treatments.

About 1 in 3000 children is born with cystic fibrosis (CF) in the US every year. It is a fatal disease that is caused by a defective gene that produces a misshapen form of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR). Because their bodies rapidly remove the mutant protein, people afflicted with CF do not have the necessary amount of CFTR for proper cellular functions. Specifically, protein deletion happens in a major domain of CFTR called NBD1. Previous experimental research suggests that the mutant NBD1 is more likely to misfold than normal NBD1, and the result is premature degradation of CFTR.

Team leader Nikolay Dokholyan reports that the molecular basis in CF of the increased tendency to misfold has been unknown. "Understanding molecular etiology of the disease is a key step to developing pharmaceutical strategies to fight this disease," notes Dokholyan.

The researchers used molecular dynamics simulations, which consisted of analyzing several simulations of how normal and mutant NBD1 folded. This is much like a virtual experiment, with atoms and molecules being permitted to change according to known physical laws. The virtual experiment lets researchers see how atoms actually move. Analyzing the NBD1 protein, the simulations demonstrated that the mutant NBD1 causes CF tends to misfold with greater frequency.

Further, the researchers could identify important pairs of amino acid residues that must come together in order for NBD1 to correctly fold. They identified the residues by analyzing the structures of normal and mutant NBD1 domains. Since the interactions are modulators of CFTR folding, 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."

Diminished Self-Chaperoning Activity of the DF508 Mutant of CFTR Results in Protein Misfolding
Serohijos AWR, Hegedűs T, Riordan JR, Dokholyan NV
PLoS Computational Biology (2008). 4(2): e1000008.
doi:10.1371/journal.pcbi.1000008
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Written by: Peter M Crosta
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