gabrianneivey-blog

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What are the amino acid interactions in the protein that causes Cystic Fibrosis (CF), and how do CF-causing mutations affect those interactions?

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Abstract

Statistical coupling analysis reveals alteration of amino acid interactions in Cystic Fibrosis disease causing mutations located in the NBD2 domain of CFTR

Cystic Fibrosis (CF) is an inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) ion channel. Mutations in CFTR cause impaired Cl- ion transport in the epithelial tissues of patients leading to cardiopulmonary decline and pancreatic insufficiency in severely affected patients. CFTR is composed of twelve membrane-spanning domains, two nucleotide-binding domains (NBDs), and a regulatory domain. The most common mutation in CFTR is a deletion of phenylalanine at position 508 (deltaF508) in NBD1. Previous research has primarily concentrated on the structure and dynamics of the NBD1 domain; however, numerous pathological mutations have been found in the NBD2 domain. Four independent statistical amino acid covariance algorithms were utilized to identify coupled amino acid residues in the wildtype NBD2 full multiple sequence alignment compared to mutant subsets (I1234V, S1235R, N1303K and D1270N). Our analysis reveals alterations of coupled amino acids at positions 1288 and 1345 in the full MSA compared to I1234V, N1303K, and D1270N subsets. Interestingly, the network for mutant S1235R is similar to the wildtype network and patients with this mutation present with a milder phenotype compared to the other mutants. Our results suggest the level of disruption of the coupled amino acid networks in NBD2 may correlate with severity of CF phenotypes.

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Slide Show Presentation

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