Abstract
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 language | English (US) |
|---|---|
| Article number | Article 162 |
| Journal | Frontiers in Pharmacology |
| Volume | 3 SEP |
| DOIs | |
| State | Published - 2012 |
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Keywords
- ABC transporter
- CFTR
- Cystic fibrosis
- Membrane protein structure
- Multidomain protein folding
ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology
Cite this
Development of CFTR structure. / Patrick, Anna E.; Thomas, Philip J.
In: Frontiers in Pharmacology, Vol. 3 SEP, Article 162, 2012.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Development of CFTR structure
AU - Patrick, Anna E.
AU - Thomas, Philip J.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - ABC transporter
KW - CFTR
KW - Cystic fibrosis
KW - Membrane protein structure
KW - Multidomain protein folding
UR - http://www.scopus.com/inward/record.url?scp=84867113276&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867113276&partnerID=8YFLogxK
U2 - 10.3389/fphar.2012.00162
DO - 10.3389/fphar.2012.00162
M3 - Article
C2 - 22973227
AN - SCOPUS:84867113276
VL - 3 SEP
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
M1 - Article 162
ER -