%0 Journal Article
%T Graph-Theoretic Models of Mutations in the Nucleotide Binding Domain 1 of the Cystic Fibrosis Transmembrane Conductance Regulator
%A Debra J. Knisley
%A Jeff R. Knisley
%A Andrew Cade Herron
%J Computational Biology Journal
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/938169
%X Cystic fibrosis is one of the most common inherited diseases and is caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR). This protein serves as a chloride channel and regulates the viscosity of mucus lining the ducts of a number of organs. Although much has been learned about the consequences of mutations on the energy landscape and the resulting disrupted folding pathway of CFTR, a level of understanding needed to correct the misfolding has not been achieved. The most common mutations of CFTR are located in one of two nucleotide binding domains, namely, the nucleotide binding domain 1 (NBD1). We model NBD1 using a nested graph model. The vertices in the lowest layer each represent an atom in the structure of an amino acid residue, while the vertices in the mid layer each represent the residue. The vertices in the top layer each represent a subdomain of the nucleotide binding domain. We use this model to quantify the effects of a single point mutation on the protein domain. We compare the wildtype structure with eight of the most common mutations. The graph-theoretic model provides insight into how a single point mutation can have such profound structural consequences. 1. Introduction Cystic fibrosis is the most common genetic disorder in the Caucasian population. Cystic fibrosis (CF) is caused by a single point mutation in the cystic fibrosis membrane conductance regulator (CFTR) protein [1¨C4]. CFTR is a chloride channel located in the apical membrane of epithelial cells and plays a fundamental role in transepithelial salt and water movement [5]. A mutation of this protein affects a number of organs in the body such as lungs, pancreas, reproductive organs, and colon. The viscosity of the mucus that lines the ducts of these organs is altered by the increased salt levels resulting in sticky mucus plugs that disrupt the normal function of these organs. A mutation in the CFTR protein occurs in approximately one in every twenty individuals in the Caucasian population and there are more than one thousand nine hundred different reported mutations of CFTR resulting in different levels of severity of clinical consequences [6]. Although there are a large number of reported mutations of CFTR, the deletion of phenylalanine at position 508 (¦¤F508) occurs in more than 90% of the CF population [7]. The ¦¤F508 mutation prevents the correct folding of the protein and consequential degradation [7, 8]. Thus, this mutation results in one of the more severe phenotypes. Once considered a fatal disease, knowledge about
%U http://www.hindawi.com/journals/cbj/2013/938169/