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CFTR: Structural Mishap by Mutation
Author(s) -
Link T,
Arpornsukant P,
Chareddy A,
Alluri A,
Chyong D,
Eshleman C,
Hu M,
Jain S,
Kahn J,
Kemelmakher H,
Kepner A,
Krishnaswamy A,
Raman V,
Sanders K,
Stock G
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb64
Subject(s) - cystic fibrosis transmembrane conductance regulator , mutation , cyclic nucleotide binding domain , chloride channel , cystic fibrosis , endoplasmic reticulum , atp binding cassette transporter , transmembrane domain , chemistry , microbiology and biotechnology , amino acid , biology , biochemistry , genetics , peptide sequence , gene , transporter
The CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) protein is a member of the ABC (ATP‐binding cassette) family, which functions as a low conductance channel regulating the flow of certain anions (especially chloride and thiocyanate) across membranes of epithelial cells, allowing for osmosis‐based regulation of mucus consistency. The proper function of CFTR depends on the amino acid phenylalanine at position 508, which mediates a tertiary interaction between the surface of the N‐terminal nucleotide‐binding domain and cytoplasmic loop‐4 in the C‐terminal membrane‐spanning domain. Miscoding caused by the most common identified mutation, ΔF508, results in loss of phenylalanine by deletion of base pairs G, A, and A from the sequence “T‐A‐G” at position 507 and adjacent “A‐A‐A”, resulting in a codon made for isoleucine, but not for phenylalanine. Inheritance of two copies of the mutation causes part of the CFTR protein to misfold and degrade, not becoming fully processed in the endoplasmic reticulum. This mutation, among others, leads to a class II mutation of cystic fibrosis. The misfolded CFTR is either not transported to the surface of the membrane or is only transported in residual amounts, preventing the regulation of mucus consistency and causes cystic fibrosis. The mechanism of the ATP‐dependent gating mutation in CFTR protein can be further understood through modeling. Understanding the mutation that causes the misfolding of CFTR can help develop new treatments for those afflicted with cystic fibrosis. Walton High School SMART (Students Modeling A Research Topic) Team has designed a model of CFTR using 3D printing technology to investigate structure‐function relationships.