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Calnexin is a [[Chaperone (protein)|chaperone]], characterized by assisting [[protein folding]] and quality control, ensuring that only properly folded and assembled proteins proceed further along the [[secretory pathway]]. It specifically acts to retain unfolded or unassembled N-linked [[glycoproteins]] in the ER.<ref name= "Ou">{{cite journal | vauthors = Ou WJ, Cameron PH, Thomas DY, Bergeron JJ | title = Association of folding intermediates of glycoproteins | journal = Nature | volume = 364 | issue = 644 | pages = 771–6 | year = 1993 | pmid = 8102790 | doi = 10.1038/364771a0 }}</ref>
Calnexin binds only those N-[[glycoprotein]]s that have GlcNAc2Man9Glc1 [[oligosaccharide]]s.<ref name= "Hammond">{{cite journal | vauthors = Hammond C, Braakman I, Helenius A | title = Role of N-linked oligosaccharide recognition, glucose trimming, and calnexin in glycoprotein folding and quality control | journal = Proc Natl Acad Sci USA | volume = 91 | issue = 3 | pages = 913–7 | year = 1984 | pmid = 8302866 | pmc = 521423 | doi = 10.1073/pnas.91.3.913 }}</ref> These monoglucosylated oligosaccharides result from the trimming of two glucose residues by the sequential action of two [[glucosidase]]s, I and II. Glucosidase II can also remove the third and last glucose residue. If the glycoprotein is not properly folded, an enzyme called [[UGGT]] (for UDP-glucose:glycoprotein glucosyltransferase) will add the glucose residue back onto the oligosaccharide thus regenerating the glycoprotein's ability to bind to calnexin.<ref name= "Gañán">{{cite journal | vauthors = Gañán S, Cazzulo JJ, Parodi AJ | title = A major proportion of N-glycoproteins are transiently glucosylated in the endoplasmic reticulum | journal = Biochemistry | volume = 30 | issue = 12 | pages = 3098–104 | year = 1991 | pmid = 1826090 | doi=10.1021/bi00226a017}}</ref> The improperly-folded glycoprotein chain thus loiters in the ER and the expression of EDEM/Htm1p <ref name= "Jacob">{{cite journal | vauthors = Jacob CA, Bodmer D, Spirig U, Battig P, Marcil A, Dignard D, Bergeron JJ, Thomas DY, Aebi M | title = Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast | journal = EMBO Rep | volume = 2| issue = 5 | pages = 423–30| year = 2001 | pmid = 11375935 | pmc = 1083883 | doi = 10.1093/embo-reports/kve089 }}</ref><ref name= "Hosokawa">{{cite journal | vauthors = Hosokawa N, Wada I, Hasegawa K, Yorihuzi T, Tremblay LO, Herscovics A, Nagata K | title = A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation | journal = EMBO Rep | volume = 2| issue = 5 | pages = 415–2| year = 2001 | pmid = 11375934 | pmc = 1083879 | doi=10.1093/embo-reports/kve084}}</ref><ref name= "Lee">{{cite journal | vauthors = Lee AH, Iwakoshi NN, Glimcher LH | title = XBP-1 regulates a subset of endoplasmic reticulum chaperone genes in the unfolded protein response | journal = Mol Cell Biol | volume = 23| issue = 21 | pages = 5448–59| year = 2003 | pmid = 14559994 | pmc = 207643 | doi = 10.1128/mcb.23.21.7448-7459.2003 }}</ref> which eventually sentences the underperforming glycoprotein to [[Chemical decomposition|degradation]] by removing one of the nine [[mannose]] residues. The mannose lectin Yos-9 (OS-9 in humans) marks and sorts misfolded glycoproteins for degradation. Yos-9 recognizes mannose residues exposed after α-mannosidase removal of an outer mannose of misfolded glycoproteins.<ref name= "Quan">{{cite journal | vauthors = Quan EM, Kamiya D, Denic V, Weibezahn J, Kato K, Weissman JS | title = Defining the glycan destruction signal for endoplasmic reticulum-associated degradation | journal = Mol Cell | volume = 32| issue = 6 | pages = 870–7| year = 2008 | pmid = 19111666 | pmc = 2873636 | doi=10.1016/j.molcel.2008.11.017}}</ref>▼
▲These monoglucosylated oligosaccharides result from the trimming of two glucose residues by the sequential action of two [[glucosidase]]s, I and II. Glucosidase II can also remove the third and last glucose residue. If the glycoprotein is not properly folded, an enzyme called [[UGGT]] (for UDP-glucose:glycoprotein glucosyltransferase) will add the glucose residue back onto the oligosaccharide thus regenerating the glycoprotein's ability to bind to calnexin.<ref name= "Gañán">{{cite journal | vauthors = Gañán S, Cazzulo JJ, Parodi AJ | title = A major proportion of N-glycoproteins are transiently glucosylated in the endoplasmic reticulum | journal = Biochemistry | volume = 30 | issue = 12 | pages = 3098–104 | year = 1991 | pmid = 1826090 | doi=10.1021/bi00226a017}}</ref> The improperly-folded glycoprotein chain thus loiters in the ER and the expression of EDEM/Htm1p <ref name= "Jacob">{{cite journal | vauthors = Jacob CA, Bodmer D, Spirig U, Battig P, Marcil A, Dignard D, Bergeron JJ, Thomas DY, Aebi M | title = Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast | journal = EMBO Rep | volume = 2| issue = 5 | pages = 423–30| year = 2001 | pmid = 11375935 | pmc = 1083883 | doi = 10.1093/embo-reports/kve089 }}</ref><ref name= "Hosokawa">{{cite journal | vauthors = Hosokawa N, Wada I, Hasegawa K, Yorihuzi T, Tremblay LO, Herscovics A, Nagata K | title = A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation | journal = EMBO Rep | volume = 2| issue = 5 | pages = 415–2| year = 2001 | pmid = 11375934 | pmc = 1083879 | doi=10.1093/embo-reports/kve084}}</ref><ref name= "Lee">{{cite journal | vauthors = Lee AH, Iwakoshi NN, Glimcher LH | title = XBP-1 regulates a subset of endoplasmic reticulum chaperone genes in the unfolded protein response | journal = Mol Cell Biol | volume = 23| issue = 21 | pages = 5448–59| year = 2003 | pmid = 14559994 | pmc = 207643 | doi = 10.1128/mcb.23.21.7448-7459.2003 }}</ref> which eventually sentences the underperforming glycoprotein to [[Chemical decomposition|degradation]] by removing one of the nine [[mannose]] residues. The mannose lectin Yos-9 (OS-9 in humans) marks and sorts misfolded glycoproteins for degradation. Yos-9 recognizes mannose residues exposed after α-mannosidase removal of an outer mannose of misfolded glycoproteins.<ref name= "Quan">{{cite journal | vauthors = Quan EM, Kamiya D, Denic V, Weibezahn J, Kato K, Weissman JS | title = Defining the glycan destruction signal for endoplasmic reticulum-associated degradation | journal = Mol Cell | volume = 32| issue = 6 | pages = 870–7| year = 2008 | pmid = 19111666 | pmc = 2873636 | doi=10.1016/j.molcel.2008.11.017}}</ref>
Calnexin associates with the protein folding enzyme ERp57
After the β2-microglobulin binds to the MHC class I peptide-loading complex (PLC), calreticulinand ERp57 take over the job of chaperoning the MHC class I protein while the tapasin links the complex to the
A prolonged association of calnexin with mutant misfolded PMP22 known to cause [[Charcot–Marie–Tooth disease|Charcot-Marie-Tooth Disease]] <ref name= "Dickson">{{cite journal | vauthors = Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, Thomas DY, Snipes GJ | title = Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for "gain-of-function" ER diseases | journal = Proc Natl Acad Sci USA | volume = 99 | issue = 15 | pages = 9852–7 | year = 2002 | pmid = 12119418 | pmc = 125041 | doi = 10.1073/pnas.152621799 }}</ref> leads to the sequestration, degradation and inability of PMP22 to traffic to the [[Schwann cell]] surface for [[myelination]]. After repeated rounds of calnexin binding, mutant PMP22 is modified by [[ubiquitin]] for degradation by the [[proteasome]] as well as a Golgi to ER retrieval pathway to return any misfolded PMP22 that escaped from the ER to the Golgi apparatus.<ref name= "Hara">{{cite journal | vauthors = Hara T, Hashimoto Y, Akuzawa T, Hirai R, Kobayashi H, Sato K | title = Rer1 and calnexin regulate endoplasmic reticulum retention of a peripheral myelin protein 22 mutant that causes type 1A Charcot-Marie-Tooth disease | journal = Sci Rep | volume = 4 | issue = | pages = 1–11 | year = 2014 | pmid = 25385046 | pmc = 4227013 | doi=10.1038/srep06992}}</ref>
The x-ray crystal structure of calnexin revealed a globular lectin domain and a long hydrophobic arm extending out
== Cofactors ==
[[Adenosine triphosphate|ATP]] and [[Ca++|calcium ions]] are
== References ==
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