Premium
An unstable transmembrane segment in the cystic fibrosis transmembrane conductance regulator
Author(s) -
Tector Matthew,
Hartl F. Ulrich
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.22.6290
Subject(s) - cystic fibrosis transmembrane conductance regulator , transmembrane protein , translocon , biology , endoplasmic reticulum , microbiology and biotechnology , membrane protein , chloride channel , transmembrane domain , biogenesis , ion channel , biochemistry , membrane , receptor , gene
The cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel with 12 membrane‐spanning sequences, undergoes inefficient maturation in the endoplasmic reticulum (ER). Potentially charged residues in transmembrane segments may contribute to this defect in biogenesis. We demonstrate that transmembrane segment 6 of CFTR, which contains three basic amino acids, is extremely unstable in the lipid bilayer upon membrane insertion in vitro and in vivo . However, two distinct mechanisms counteract this anchoring deficiency: (i) the ribosome and the ER translocon co‐operate to prevent transmembrane segment 6 from passing through the membrane co‐ translationally; and (ii) cytosolic domains of the ion channel post‐translationally maintain this segment of CFTR in a membrane‐spanning topology. Although these mechanisms are essential for successful completion of CFTR biogenesis, inefficiencies in their function retard the maturation of the protein. It seems possible that some of the disease‐causing mutations in CFTR may reduce the efficiency of proper membrane anchoring of the protein.