CFTR and cystic fibrosis: From our results on the V232D mutation of CFTR, we propose—based on current models of full-length CFTR biogenesis13 (Fig. 3b, upper row)—a mechanistic model of V232D CF pathogenesis in which the free-energy penalty due to an anionic residue in TM4 impairs membrane insertion of the TM3/4 helical hairpin, thereby disrupting the native topology of the channel protein (Fig. 3b, middle row).