TY - JOUR T1 - Diminished Self-Chaperoning Activity of the ΔF508 Mutant of CFTR Results in Protein Misfolding A1 - Serohijos, Adrian W. R. A1 - Hegedűs, Tamás A1 - Riordan, John R. A1 - Dokholyan, Nikolay V. Y1 - 2008/02/29 N2 - Author SummaryDeletion of a single residue, phenylalanine at position 508, in the first nucleotide binding domain (NBD1) of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is present in approximately 90% of cystic fibrosis (CF) patients. Experiments show that this mutant protein exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant incorrect interactions of other domains. However, little is known about the direct effect of the Phe508 deletion on NBD1 folding. Here, using molecular dynamics simulations of NBD1-WT, NBD1-F508A, and NBD1-ΔF508, we show that the deletion of Phe508 indeed alters the kinetics of NBD1 folding. We also find that the intermediate states appearing on wild type and mutant folding pathways are populated differently and that their kinetic accessibilities are distinct. Moreover, we identified critical interactions not necessarily localized near position 508, such as Q493/P574 and F575/F587, to be significant structural elements influencing the kinetic difference between wild type and mutant NBD1. We propose that these observed alterations in folding kinetics of mutant NBD1 result in misassembly of the whole multi-domain protein, thereby causing its premature degradation. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 4 IS - 2 UR - https://doi.org/10.1371/journal.pcbi.1000008 SP - e1000008 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1000008 ER -