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A more recent version of this article appeared on November 1, 2008
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Submitted on April 6, 2008
Accepted on August 8, 2008
Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Monitoring Editor: Jeffrey L. Brodsky
CFTR is a polytopic membrane protein that functions as a Cl- channel and consists of 2 membrane spanning domains (MSD), 2 cytosolic nucleotide binding domains (NBD) and a cytosolic regulatory domain. Cytosolic Hsp70, and ER localized calnexin are chaperones that facilitate CFTR biogenesis. Hsp70 functions in both the cotranslational folding and post-translational degradation of CFTR. Yet, the mechanism for calnexin action in folding and quality control of CFTR is not clear. Investigation of this question revealed that calnexin is not essential for CFTR or CFTR
F508 degradation. We identified a dependence on calnexin for proper assembly of CFTR’s membrane spanning domains. Interestingly, efficient folding of NBD2 was also found to be dependent upon calnexin binding to CFTR. Furthermore, we identified folding defects caused by deletion of F508 that occurred before and after the calnexin dependent association of MSD1 and MSD2. Early folding defects are evident upon translation of the NBD1 and R-domain and are sensed by the RMA-1 ubiquitin ligase complex. Keywords: CFTR, calnexin, Hsp70, castanospermine, membrane domain assembly, quality control
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