Biochemical implications of sequence comparisons of the cystic fibrosis transmembrane conductance regulator.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is both of medical significance in humans and of interest with regard to osmoregulation in aquatic organisms. CFTR is composed of five domains: two membrane-spanning domains, two nucleotide-binding domains, and a regulatory domain. Notwithstanding the plethora of information concerning the structure and function of CFTR, the biochemistry of many facets of CFTR are not completely understood. In this regard, we have performed a sequence alignment of representative vertebrate CFTR with the aim of generating hypotheses on the functional significance of conserved and variable residues. Postulates on function common to all organisms are: (i) Thr338 in the sixth transmembrane segment could have a function related to that of the pore-lining residue Lys335, and it is possible that Thr338 hydrogen bonds to Lys335, thus indirectly affecting anion permeability; (ii) the fragment (111)PDNKE could be an ion sensor; (iii) motifs in the two nucleotide-binding domains reflect differential ATP binding and hydrolysis; and (iv) an interaction in the R domain involving (765)RRQSVL and the C terminal end of the domain results in an inhibitory conformation. Major adaptations in fishes include variations in the postulated ion sensor (111)PDNKE, and the absence of a proline residue in the R domain with consequent higher chloride efflux.
Tan
Agnes L C
AL
Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Republic of Singapore. mcbtanlc@imcb.nus.edu.sg
Ong
Serene A K
SA
Venkatesh
Byrappa
B
D000255:Adenosine Triphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D005399:Fishes; D006801:Humans; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014882:Water-Electrolyte Balance
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate