Development of CFTR structure

Anna E. Patrick, Philip J. Thomas

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Cystic fibrosis is a lethal genetic disease caused by lack of functional cystic fibrosis transmembrane conductance regulator (CFTR) proteins at the apical surface of secretory epithelia. CFTR is a multidomain protein, containing five domains, and its functional structure is attained in a hierarchical folding process. Most CF-causing mutations in CFTR, including the most common mutation, a deletion of phenylalanine at position 508 ({increment}F508), are unable to properly fold into this functional native three dimensional structure. Currently, no highresolution structural information about full length CFTR exists. However, insight has been gained through examining homologous ABC transporter structures, molecular modeling, and high-resolution structures of individual, isolated CFTR domains. Taken together, these studies indicate that the prevalent δF508 mutation disrupts two essential steps during the development of the native structure: folding of the first nucleotide binding domain (NBD1) and its later association with the fourth intracellular loop (ICL4) in the second transmembrane domain (TMD2). Therapeutics to rescue {increment}F508 and other mutants in CFTR can be targeted to correct defects that occur during the complex folding process. This article reviews the structural relationships between CFTR and ABC transporters and current knowledge about how CFTR attains its structure-with a focus on how this process is altered by CF-causing mutations in a manner targetable by therapeutics.

Original languageEnglish (US)
Article numberArticle 162
JournalFrontiers in Pharmacology
Volume3 SEP
StatePublished - 2012


  • ABC transporter
  • CFTR
  • Cystic fibrosis
  • Membrane protein structure
  • Multidomain protein folding

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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