Pathway Map Details

CFTR folding and maturation (norm and CF)

view in full size
| open in MetaCore

Object list (links open in MetaCore):

DNAJB6 (Hdj-1), HSP70, CFTR, CFTR, MA1B1, HSPBP1, Aha1, HSP90 beta, Calnexin, CFTR, HSP40, CFTR, Hdj-2, HSP90 alpha, EDEM, CFTR, OST complex, CFTR, CFTR, UGCGL1, CFTR


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 [1], [2], [3]. The most common CFTR mutation is loss of a Phe residue at position 508 ( deltaF508-CFTR ) [4].

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 wt- CFTR or 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) [5]. This process is known as N-glycosylation or core-glycosylation (see in detail about N-glycosylation [6] and OST complex [7], [8] ).

Then, most of deltaF508- CFTR is degraded via Heat shock 70kDa protein 8 (Hsc70)-dependent ubiquitination. Unlike deltaF508- CFTR, wt- CFTR 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 [5], [9].

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 ) [10], [11] and others [12]. 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 [13]. The exact role of most chaperones is unknown [12].

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 [5], [9].

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) [5], [9]. GERAD is a major degradative pathway for misfolded CFTR.


  1. Kogan I, Ramjeesingh M, Li C, Kidd JF, Wang Y, Leslie EM, Cole SP, Bear CE
    CFTR directly mediates nucleotide-regulated glutathione flux. The EMBO journal 2003 May 1;22(9):1981-9
  2. Chan HC, Shi QX, Zhou CX, Wang XF, Xu WM, Chen WY, Chen AJ, Ni Y, Yuan YY
    Critical role of CFTR in uterine bicarbonate secretion and the fertilizing capacity of sperm. Molecular and cellular endocrinology 2006 May 16;250(1-2):106-13
  3. Gadsby DC, Vergani P, Csanady L
    The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 2006 Mar 23;440(7083):477-83
  4. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  5. Amaral MD
    Processing of CFTR: traversing the cellular maze--how much CFTR needs to go through to avoid cystic fibrosis? Pediatric pulmonology 2005 Jun;39(6):479-91
  6. Popov M, Tam LY, Li J, Reithmeier RA
    Mapping the ends of transmembrane segments in a polytopic membrane protein. Scanning N-glycosylation mutagenesis of extracytosolic loops in the anion exchanger, band 3. The Journal of biological chemistry 1997 Jul 18;272(29):18325-32
  7. Kelleher DJ, Karaoglu D, Mandon EC, Gilmore R
    Oligosaccharyltransferase isoforms that contain different catalytic STT3 subunits have distinct enzymatic properties. Molecular cell 2003 Jul;12(1):101-11
  8. Shibatani T, David LL, McCormack AL, Frueh K, Skach WR
    Proteomic analysis of mammalian oligosaccharyltransferase reveals multiple subcomplexes that contain Sec61, TRAP, and two potential new subunits. Biochemistry 2005 Apr 26;44(16):5982-92
  9. Farinha CM, Amaral MD
    Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin. Molecular and cellular biology 2005 Jun;25(12):5242-52
  10. Loo MA, Jensen TJ, Cui L, Hou Y, Chang XB, Riordan JR
    Perturbation of Hsp90 interaction with nascent CFTR prevents its maturation and accelerates its degradation by the proteasome. The EMBO journal 1998 Dec 1;17(23):6879-87
  11. Farinha CM, Nogueira P, Mendes F, Penque D, Amaral MD
    The human DnaJ homologue (Hdj)-1/heat-shock protein (Hsp) 40 co-chaperone is required for the in vivo stabilization of the cystic fibrosis transmembrane conductance regulator by Hsp70. The Biochemical journal 2002 Sep 15;366(Pt 3):797-806
  12. Wang X, Venable J, Lapointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, Kellner W, Matteson J, Plutner H, Riordan JR, Kelly JW, Yates JR 3rd, Balch WE
    Hsp90 Cochaperone Aha1 Downregulation Rescues Misfolding of CFTR in Cystic Fibrosis. Cell 2006 Nov 17;127(4):803-15
  13. McLellan CA, Raynes DA, Guerriero V
    HspBP1, an Hsp70 cochaperone, has two structural domains and is capable of altering the conformation of the Hsp70 ATPase domain. The Journal of biological chemistry 2003 May 23;278(21):19017-22