the primary folding defect and rescue of δf508 cftr emerge during translation of the mutant domain主要的折叠缺陷和救援突变的cftrδf508检测出现在翻译领域.pdfVIP

The Primary Folding Defect and Rescue of DF508 CFTR Emerge during Translation of the Mutant Domain 1. 1. 2 2¤ 1 Hanneke Hoelen , Bertrand Kleizen , Andre Schmidt , John Richardson , Paraskevi Charitou , 2 1 Philip J. Thomas , Ineke Braakman * 1 Department of Chemistry, Faculty of Science, Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands, 2 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America Abstract In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis, as soon as NBD1 is translated. Introduction of either the I539T or G550E suppressor mutation in NBD1 partially rescues DF508 CFTR to the cell surface, but only I539T repaired DF508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length DF508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of DF508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis. Citation: Hoelen H, Kleizen B, Schmidt A, Richardson J, Charitou P, et al. (2010) The Primary Folding Defect and Rescue of DF508 CFTR Emerge during Translation of the Mutant Domain. PLoS ONE 5(11): e15458. doi:10.1371/journal.pone.0015458 Editor: Vladimir N. Uversky, University of South Florida College of Medicine, United States of America Rece