Identification of a region of strong discrimination in the pore of CFTR

The variety of methods used to identify the structural determinants of anio n selectivity in the cystic fibrosis transmembrane conductance regulator Cl - channel has made it difficult to assemble the data into a coherent framew ork that describes the three-dimensional structure of the pore. Here, we co mpare the relative importance of sites previously studied and identify new sites that contribute strongly to anion selectivity. We studied Cl- and sub stitute anions in oocytes expressing, wild-type cystic fibrosis transmembra ne conductance regulator or 12-pore-domain mutants to determine relative pe rmeability and relative conductance for 9 monovalent anions and 1 divalent anion. The data indicate that the region of strong discrimination resides b etween T338 and S341 in transmembrane 6, where mutations affected selectivi ty between Cl- and both large and small anions. Mutations further toward th e extracellular end of the pore only strongly affected selectivity between Cl- and larger anions. Only mutations at S341 affected selectivity between monovalent and divalent anions. The data are consistent with a narrowing of the pore between the extracellular end and a constriction near the middle of the pore.