Topological model of membrane domain of the cystic fibrosis transmembrane conductance regulator

The cystic fibrosis transmembrane conductance regulator is a cAMP-regulated chloride channel, We used molecular modelling to predict 3-D models for the CFTR membrane domain. Hydropathy and residue conservation in all CFTRs as well as in other proteins suggested that the membrane domain is a 12-helix bundle. If the domain is enclosing a channel for chloride, it could be made of five helices. Wt propose two structural models in which both lumenal and cytoplasmic entrances to the chloride pore have a ring of positively charged residues, The inner surface of the channel is covered with neutral polar pills one or two charged residues. Helices that are nor directly involved in the chloride channel could organise to form a second channel; a dimeric symmetrical structure is proposed. Analysis raised interest for helix 5: this hydrophobic fragment is conserved in all CFTRs and aligns with segments present in several different ion channels and transporters. The existence of an FFXXFFXXF motif is proposed. Helix 5 could be an important domain of CFTRs. The models agree with available data from pathological mutations but does not account for the membrane insertion of a hydrophilic fragment of NBD1. (C) 1998 by Elsevier Science Inc.