Lectin control of protein folding and sorting in the secretory pathway

Schrag, Joseph D.; Procópio, Daniela O.; Cygler, Mirosław; Thomas, David Y.; Bergeron, John J.M.

doi:10.1016/s0968-0004(02)00004-x

Cited by 172 publications

(106 citation statements)

References 66 publications

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“…Our view of protein maturation and routing has grown more complex as we have come to understand the roles that pro-proteins, post-translational modifications, and the quality control system play along with the endogenous chaperone proteins that assist in folding and serve to identify and retain misfolded proteins (Schrag et al, 2003;Kleizen and Braakman, 2004;Castro-Fernandez et al, 2005). One notable feature is that the recognition of "defective" mutant proteins is based on common features of misfolded proteins (i.e.…”

Section: Discussionmentioning

confidence: 99%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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SUMMARYAll reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct mis-folding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

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Section: Discussionmentioning

confidence: 99%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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“…This would prolong "off-time" duration of the CFTR from the reglucosylation-mediated calnexin cycle (Parodi, 2000;Cabral et al, 2001;Schrag et al, 2003) Figure 6. Concentric membranous body of the ER is connected to the late secretory pathway.…”

Section: Discussionmentioning

confidence: 99%

“…In this model, misfolded moiety of CFTR should be responsible for the association. Currently, we were unable to exclude the possibility, however, we think it unlikely because 1) CM body is a dynamic structure (Figures 4, I and J, and 6) so that once-bound CFTR should be dissociated from the CM body; and 2) no cellular factor has been identified to release the substrate from calnexin other than glucosidase II, despite the extensive studies on the ER quality control (Ellgaard and Helenius, 2003;Schrag et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

ΔF508 CFTR Pool in the Endoplasmic Reticulum Is Increased by Calnexin Overexpression

Okiyoneda

Harada

Takeya³

et al. 2004

MBoC

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The most common cystic fibrosis transmembrane conductance regulator (CFTR) mutant in cystic fibrosis patients, ⌬F508 CFTR, is retained in the endoplasmic reticulum (ER) and is consequently degraded by the ubiquitin-proteasome pathway known as ER-associated degradation (ERAD). Because the prolonged interaction of ⌬F508 CFTR with calnexin, an ER chaperone, results in the ERAD of ⌬F508 CFTR, calnexin seems to lead it to the ERAD pathway. However, the role of calnexin in the ERAD is controversial. In this study, we found that calnexin overexpression partially attenuated the ERAD of ⌬F508 CFTR. We observed the formation of concentric membranous bodies in the ER upon calnexin overexpression and that the ⌬F508 CFTR but not the wild-type CFTR was retained in the concentric membranous bodies. Furthermore, we observed that calnexin overexpression moderately inhibited the formation of aggresomes accumulating the ubiquitinated ⌬F508 CFTR. These findings suggest that the overexpression of calnexin may be able to create a pool of ⌬F508 CFTR in the ER. INTRODUCTIONCystic fibrosis transmembrane conductance regulator (CFTR) is a polytopic integral membrane protein that functions as a cAMP-dependent Cl Ϫ channel in the apical membrane of epithelial cells (Anderson et al., 1991;Drumm et al., 1991;Tabcharani et al., 1991;Bear et al., 1992). Mutations in the CFTR gene lead to the absence or malfunction of a regulated Cl Ϫ channel in the apical membrane of secretory epithelia, resulting in the clinical symptoms of cystic fibrosis (CF) (Kerem et al., 1989;Riordan et al., 1989;Rommens et al., 1989;Cheng et al., 1990). Therefore, potential CF therapies are aimed at overcoming the functional impairment of various mutant CFTRs, particularly ⌬F508 CFTR, in which a phenylalanine at position 508 is deleted from the first nucleotide-binding fold. This mutation is found in ϳ70% of CF chromosomes and results in a severe form of the disease; Ͼ90% of CF patients have at least one ⌬F508 allele (Tsui, 1992;Sferra and Collins, 1993). Although ⌬F508 CFTR is functionally competent as a cAMP-dependent Cl Ϫ channel in model situations where it reaches the plasma membrane (Drumm et al., 1991;Denning et al., 1992;Li et al., 1993), in mammalian cells ⌬F508 CFTR fails to reach the plasma membrane.CFTR biogenesis is inefficient. During insertion into the ER membrane, CFTR interacts with the cytosolic chaperones Hsc70/Hdj-2 and Hsp90, as well as the ER chaperone calnexin (CNX) (Yang et al., 1993;Pind et al., 1994;Loo et al., 1998;Meacham et al., 1999). After ATP-dependent conformational maturation, assisted by cytosolic and ER chaperones, the chaperones release CFTR, and only ϳ30% of the immature wild-type (wt) CFTR transits to the late secretory pathway, ultimately reaching the plasma membrane (Lukacs et al., 1994). However, most of the immature wt CFTR (ϳ70%), and nearly all of immature ⌬F508 CFTR, fail to mature and do not transit to the late secretory pathway (Lukacs et al., 1994). They are trapped in the ER as core-glycosylated products (ϳ140 kDa) and ar...

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“…The glycans add hydrophobicity to the folding peptide but also act as substrates for the lectin chaperones calnexin and calreticulin, whose role in glycoprotein folding has been extensively reviewed 5,6 . Both calnexin and calreticulin form a complex with ERp57, an ER oxidoreductase, coupling folding assistance to disulphide-bond formation.…”

Section: Disulphide-bond Formationmentioning

confidence: 99%