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Query: EC:3.6.3.44 (
P-glycoprotein
)
13,344
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cystic fibrosis transmembrane conductance regulator
(
CFTR
) is a cAMP-regulated C1(-) channel. Malfunction of
CFTR
causes cystic fibrosis (CF).
CFTR
belongs to an ATP-binding cassette (ABC) transporter superfamily which includes
P-glycoprotein
(Pgp), the molecule that is responsible for multidrug resistance in cancer cells.
P-glycoprotein
molecules have been suggested to have more than one topology and function. In this study, we analysed the early stages of membrane insertion, processing, and topology of human
CFTR
using rabbit reticulocyte lysate and wheat germ extract translation systems supplemented with canine pancreatic microsomal membranes. Our results suggest that
CFTR
contains an uncleavable signal sequence and its membrane targeting and insertion may depend on the signal recognition particle (SRP) and SRP receptor. The topology of
CFTR
in microsomal membranes is the same as the one predicted based on hydropathy plot analysis. These results, together with our previous findings on Pgp, indicate that (1) the topologies of mammalian ABC transporters can be dissected and studied using protein fusion chimeras in a cell-tree system; and (2) the membrane targeting and insertion of
CFTR
and Pgp may take the same pathway, i.e., the SRP-dependent pathway, but the membrane folding mechanism of these two proteins in microsomal membranes is probably different.
...
PMID:Membrane insertion, processing, and topology of cystic fibrosis transmembrane conductance regulator (CFTR) in microsomal membranes. 914 60
Cystic fibrosis transmembrane conductance regulator
(
CFTR
) and
P-glycoprotein
(
P-gp
) are ATP-binding cassette (ABC) transporters that have two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). Defective folding of
CFTR
lacking phenylalanine 508 (DeltaPhe508) in NBD1 is the most common cause of cystic fibrosis. The Phe508 position seems to be universally important in ABC transporters because deletion of the equivalent residue (Tyr490) in
P-gp
also inhibits maturation of the protein. The pharmacological chaperone VRT-325 can repair the DeltaPhe508-type folding defects in
P-gp
or
CFTR
. VRT-325 may repair the folding defects by promoting dimerization of the two NBDs or by promoting folding of the TMDs. To distinguish between these two mechanisms, we tested the ability of VRT-325 to promote folding of truncation mutants lacking one or both NBDs. Sensitivity to glycosidases was used as an indirect indicator of folding. It was found that VRT-325 could promote maturation of truncation mutants lacking NBD2. Truncation mutants of
CFTR
or
P-gp
lacking both NBDs showed deficiencies in core-glycosylation that could be partially reversed by carrying out expression in the presence of VRT-325. The results show that dimerization of the two NBDs to form a "nucleotide-sandwich" structure or NBD interactions with the TMDs are not essential for VRT-325 enhancement of folding. Instead, VRT-325 can promote folding of the TMDs alone. The ability of VRT-325 to promote core-glycosylation of the NBD-less truncation mutants suggests that one mechanism whereby the compound enhances folding is by promoting proper insertion of TM segments attached to the glycosylated loops so that they adopt an orientation favorable for glycosylation.
...
PMID:Modulating the folding of P-glycoprotein and cystic fibrosis transmembrane conductance regulator truncation mutants with pharmacological chaperones. 1713 88
