CFTR folding and maturation (norm and CF)
The cystic fibrosis transmembrane conductance regulator
(CFTR) is a member of the ATP-binding cassette transporter
superfamily. It acts in the apical part of the epithelial cells as a plasma-membrane
cyclic AMP-activated chloride anion, bicarbonate anion and glutathione channel , , . The most common
CFTR mutation is loss of a Phe residue at position 508
Folding and maturation of wt-CFTR and
deltaF508-CFTR are somewhat different. In both cases,
folding starts when Oligosaccharyltransferase complex (OST
complex) binds to the newly synthesized
deltaF508-CFTR via Asn-X-Ser/Thr consensus
sequences that are co-translationally inserted into the endoplasmatic reticulum (ER) by a
branched 14-unit oligosaccharide (two N-acetylglucosamines,
nine mannoses, and three glucoses) . This process is known as
N-glycosylation or core-glycosylation (see in detail about N-glycosylation  and OST complex , ).
Then, most of deltaF508-CFTR is degraded via Heat shock
70kDa protein 8 (Hsc70)-dependent ubiquitination. Unlike
proceeds in the folding pathway through an interaction of its N-glycosyl residues. Glycan
moiety is recognized by any Glucosidases I and
II, which trim two glucose residues sequentially. The exact
Glucosidases which participate in this process are unknown.
Monoglucosylated oligosaccharide structure is then recognized by the lectin
Calnexin , .
Chaperones that are currently thought to significantly affect
CFTR ER-associated folding pathways, include cytosolic
chaperones DnaJ homolog subfamily B members 1 and 6 (Hsp40
and Hdj-1), Heat shock proteins 70 and 90kDa
(Hsp70 and Hsp90) ,  and others . ATPase
activity of Hsp70 may be regulated by
Hsp70-interacting protein (HspBP1).
HspBP1 can bind Hsp70, changes
the conformation of the ATPase domain, and inhibits
Hsp70-associated protein folding . The exact
role of most chaperones is unknown .
Dissociation from Calnexin coincides with trimming of the
third glucose residue by Glucosidases II. If the
CFTR is folded at this stage, it proceeds to the secretory
pathway to Golgi. However, misfolded CFTR is specifically
recognized as such by UDP-glycoprotein glucosyltransferase (e.g.,
UGCGL1), which reglucosylates them. Reglucosylated
CFTR again may interact with Calnexin
In addition, prolonged presence in the Calnexin cycle may
cause misfolded CFTR to become a substrate of Mannosidase
alpha class 1B member 1 (MA1B1). MA1B1
removes mannose from the middle branch CFTR,
forming a Man8B isomer which in turn is recognized by another lectin ER degradation
enhancer, mannosidase alpha-like 1 (EDEM) that targets it to
proteasomal Glycoprotein endoplasmic reticulum-associated degradation (GERAD) , . GERAD is a major degradative pathway for misfolded
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