Definition of a "functional R domain" of the cystic fibrosis transmembrane conductance regulator.
The R domain of the cystic fibrosis transmembrane conductance regulator (CFTR) was originally defined as 241 amino acids, encoded by exon 13. Such exon/intron boundaries provide a convenient way to define the R domain, but do not necessarily reflect the corresponding functional domain within CFTR. A two-domain model was later proposed based on a comparison of the R-domain sequences from 10 species. While RD1, the N-terminal third of the R domain is highly conserved, RD2, the large central region of the R domain has less rigid structural requirements. Although this two-domain model was given strong support by recent functional analysis data, the simple observation that two of the four main phosphorylation sites are excluded from RD2 clearly indicates that RD2 still does not satisfy the requirements of a "functional R domain." Nevertheless, knowledge of the CFTR structure and function accumulated over the past decade and reevaluated in the context of a comprehensive sequence comparison of 15 CFTR homologues made it possible to define such a "functional R domain," i.e., amino acids C647 to D836. This definition is validated primarily because it contains all of the important potential consensus phosphorylation sequences. In addition, it includes the highly charged motif from E822 to D836. Finally, it includes all of the deletions/insertions in this region. This definition also aids in understanding the effects of missense mutations occurring within this domain.
Chen
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JM
Etablissement Français du Sang-Bretagne, Site de Brest, Brest, France.
Scotet
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D000595:Amino Acid Sequence; D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator