diminished self-chaperoning activity of the δf508 mutant of cftr results in protein misfolding减少的self-chaperoning活动δf508 cftr突变的检测结果错误折叠的蛋白质.pdfVIP

Diminished Self-Chaperoning Activity of the DF508 Mutant of CFTR Results in Protein Misfolding 1. ´ 2,3. 2,3 2 Adrian W. R. Serohijos , Tamas Hegedu˝ s , John R. Riordan , Nikolay V. Dokholyan * 1 Department of Physics and Astronomy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America, 2 Department of Biochemistry and Biophysics, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America, 3 Cystic Fibrosis Research Center, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America Abstract The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) from apical membranes of epithelial cells is responsible for cystic fibrosis (CF). Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 located in the N-terminal nucleotide binding domain (NBD1). Biochemical and cell biological studies show that the DF508 mutant exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant misassembly of other domains. However, little is known about the direct effect of the Phe508 deletion on the NBD1 folding, which is essential for rational design strategies of cystic fibrosis treatment. Here we show that the deletion of Phe508 alters the folding dynamics and kinetics of NBD1, thus possibly affecting the assembly of the complete CFTR. Using molecular dynamics simulations, we find that meta-stable intermediate states appearing on wild type and mutant folding pathways are populated differently and that the