Abstract :
[en] 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. We
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 plus one or two charged residues.
Helices that are not 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 NBDI.
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