View source for Calnexin

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{{Short description|Mammalian protein found in humans}}
{{Infobox_gene}}
'''Calnexin''' ('''CNX''') is a [https://www.uniprot.org/uniprot/P27824 67kDa] [[integral protein]] (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the [[endoplasmic reticulum]] (ER). It consists of a large (50 kDa) [[N-terminal]] [[calcium]]-[[Binding (molecular)|binding]] [[Lumen (anatomy)|lumenal]] [[protein domain|domain]], a single [[transmembrane helix]] and a short (90 [[Residue (chemistry)|residues]]), [[acid]]ic [[cytoplasm]]ic tail.<ref name= "Wada">{{cite journal | vauthors = Wada I, Rindress D, Cameron PH, Ou WJ, Doherty JJ 2nd, Louvard D, Bell AW, Dignard D, Thomas DY, Bergeron JJ | title = SSR alpha and associated calnexin are major calcium binding proteins of the endoplasmic reticulum membrane | journal = J Biol Chem| volume = 226 | issue = 29 | pages = 19599–610 | year = 1991 | doi = 10.1016/S0021-9258(18)55036-5 | pmid = 1918067 | doi-access = free }}</ref>  In humans, calnexin is encoded by the gene ''CANX''.<ref>{{cite journal|vauthors=Paskevicius T, Farraj RA, Michalak M, Agellon LB|title=Calnexin, More Than Just a Molecular Chaperone|journal=Cells|year=2023|volume=12|issue=3|page=403 |id=Article No. 403|veditors=Lim D|doi=10.3390/cells12030403|doi-access=free|pmid=36766745|pmc=9913998}}</ref>
== Function ==
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 | s2cid = 4340769 }}</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 | doi-access = free }}</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<ref name= "Zapun">{{cite journal | vauthors = Zapun A, Darby NJ, Tessier DC, Michalak M, Bergeron JJ, Thomas DY | title = Enhanced catalysis of ribonuclease B folding by the interaction of calnexin or calreticulin with ERp57 | journal = J Biol Chem | volume = 273 | issue = 211 | pages = 6009–12| year = 1998 | pmid = 9497314  | doi = 10.1074/jbc.273.11.6009 | doi-access =  free}}</ref> to catalyze glycoprotein specific disulfide bond formation and also functions as a chaperone for the folding of [[MHC class I]] α-chain in the membrane of the ER. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state.<ref name= "Bergeron">{{cite journal | vauthors = Bergeron JJ, Brenner MB, Thomas DY, Williams DB | title = Calnexin: a membrane-bound chaperone of the endoplasmic reticulum | journal = Trends Biochem Sci | volume = 19 | issue = 3 | pages = 124–8 | year = 1994 | pmid = 8203019 | doi=10.1016/0968-0004(94)90205-4}}</ref>
After the β2-microglobulin binds to the MHC class I peptide-loading complex (PLC), calreticulin and ERp57 take over the job of chaperoning the MHC class I protein while the tapasin links the complex to the [[transporter associated with antigen processing]] (TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface.
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 | bibcode = 2002PNAS...99.9852D | doi-access = free }}</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 | pages = 1–11 | year = 2014 | pmid = 25385046 | pmc = 4227013 | doi=10.1038/srep06992| bibcode = 2014NatSR...4E6992H }}</ref>
The x-ray crystal structure of calnexin revealed a globular lectin domain and a long hydrophobic arm extending out.<ref name= "Schrag">{{cite journal | vauthors = Schrag JD, Bergeron JJ, Li Y, Borisova S, Hahn M, Thomas DY, Cygler M | title = The structure of calnexin, an ER chaperone involved in quality control of protein folding | journal = Mol Cell | volume = 8 | issue = 3 | pages = 633–44 | year = 2001 | pmid = 11583625 | doi=10.1016/s1097-2765(01)00318-5| doi-access = free }}</ref>
== Cofactors ==
[[Adenosine triphosphate|ATP]] and [[Ca++|calcium ions]] are cofactors involved in substrate binding for calnexin.<ref name= "Thomas">{{cite journal | vauthors = Ou WJ, Bergeron JJ, Li Y, Kang CY, Thomas DY | title = Conformational changes induced in the endoplasmic reticulum luminal domain of calnexin by Mg-ATP and Ca2+ | journal = J Biol Chem | volume = 270 | issue = 30 | pages = 18051–9 | year = 1995 | pmid = 7629114 | doi=10.1074/jbc.270.30.18051| doi-access = free }}</ref>
== References ==
{{reflist}}
== External links ==
* {{MeshName|Calnexin}}
== Further reading ==
{{refbegin | 2}}
* {{cite book | vauthors = Benyair R, Ron E, Lederkremer GZ | title = Protein quality control, retention, and degradation at the endoplasmic reticulum | volume = 292 | pages = 197–280 | year = 2011 | pmid = 22078962 | doi = 10.1016/B978-0-12-386033-0.00005-0 | series = International Review of Cell and Molecular Biology | isbn = 9780123860330 }}
* {{cite journal | vauthors = Del Bem LE | title = The evolutionary history of calreticulin and calnexin genes in green plants | journal = Genetica | volume = 139 | issue = 2 | pages = 225–9  | date = Feb 2011 | pmid = 21222018 | doi = 10.1007/s10709-010-9544-y | s2cid = 9228786 }}
* {{cite journal | vauthors = Kleizen B, Braakman I | title = Protein folding and quality control in the endoplasmic reticulum | journal = Current Opinion in Cell Biology | volume = 16 | issue = 4 | pages = 343–9  | date = Aug 2004 | pmid = 15261665 | doi = 10.1016/j.ceb.2004.06.012 | hdl = 1874/5106 | hdl-access = free }}
* {{cite journal | vauthors = Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J | title = Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes | journal = Electrophoresis | volume = 13 | issue = 12 | pages = 960–9  | date = Dec 1992  | pmid = 1286667 | doi = 10.1002/elps.11501301199 | s2cid = 41855774 }}
* {{cite journal | vauthors = Galvin K, Krishna S, Ponchel F, Frohlich M, Cummings DE, Carlson R, Wands JR, Isselbacher KJ, Pillai S, Ozturk M | title = The major histocompatibility complex class I antigen-binding protein p88 is the product of the calnexin gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 18 | pages = 8452–6  | date = Sep 1992 | pmid = 1326756 | pmc = 49938 | doi = 10.1073/pnas.89.18.8452 | bibcode = 1992PNAS...89.8452G | doi-access = free }}
* {{cite journal | vauthors = Pind S, Riordan JR, Williams DB | title = Participation of the endoplasmic reticulum chaperone calnexin (p88, IP90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator | journal = The Journal of Biological Chemistry | volume = 269 | issue = 17 | pages = 12784–8  | date = Apr 1994 | doi = 10.1016/S0021-9258(18)99944-8 | pmid = 7513695 | doi-access = free }}
* {{cite journal | vauthors = Honoré B, Rasmussen HH, Celis A, Leffers H, Madsen P, Celis JE | title = The molecular chaperones HSP28, GRP78, endoplasmin, and calnexin exhibit strikingly different levels in quiescent keratinocytes as compared to their proliferating normal and transformed counterparts: cDNA cloning and expression of calnexin | journal = Electrophoresis | volume = 15 | issue = 3–4 | pages = 482–90 | year = 1992 | pmid = 8055875 | doi = 10.1002/elps.1150150166 | s2cid = 22393279 }}
* {{cite journal | vauthors = Tjoelker LW, Seyfried CE, Eddy RL, Byers MG, Shows TB, Calderon J, Schreiber RB, Gray PW | title = Human, mouse, and rat calnexin cDNA cloning: identification of potential calcium binding motifs and gene localization to human chromosome 5 | journal = Biochemistry | volume = 33 | issue = 11 | pages = 3229–36  | date = Mar 1994 | pmid = 8136357 | doi = 10.1021/bi00177a013 }}
* {{cite journal | vauthors = Lenter M, Vestweber D | title = The integrin chains beta 1 and alpha 6 associate with the chaperone calnexin prior to integrin assembly | journal = The Journal of Biological Chemistry | volume = 269 | issue = 16 | pages = 12263–8  | date = Apr 1994 | doi = 10.1016/S0021-9258(17)32710-2 | pmid = 8163531 | doi-access = free }}
* {{cite journal | vauthors = Rajagopalan S, Xu Y, Brenner MB | title = Retention of unassembled components of integral membrane proteins by calnexin | journal = Science | volume = 263 | issue = 5145 | pages = 387–90  | date = Jan 1994 | pmid = 8278814 | doi = 10.1126/science.8278814 | bibcode = 1994Sci...263..387R }}
* {{cite journal | vauthors = David V, Hochstenbach F, Rajagopalan S, Brenner MB | title = Interaction with newly synthesized and retained proteins in the endoplasmic reticulum suggests a chaperone function for human integral membrane protein IP90 (calnexin) | journal = The Journal of Biological Chemistry | volume = 268 | issue = 13 | pages = 9585–92  | date = May 1993 | doi = 10.1016/S0021-9258(18)98391-2 | pmid = 8486646 | doi-access = free }}
* {{cite journal | vauthors = Bellovino D, Morimoto T, Tosetti F, Gaetani S | title = Retinol binding protein and transthyretin are secreted as a complex formed in the endoplasmic reticulum in HepG2 human hepatocarcinoma cells | journal = Experimental Cell Research | volume = 222 | issue = 1 | pages = 77–83  | date = Jan 1996 | pmid = 8549676 | doi = 10.1006/excr.1996.0010 | doi-access = free }}
* {{cite journal | vauthors = Otteken A, Moss B | title = Calreticulin interacts with newly synthesized human immunodeficiency virus type 1 envelope glycoprotein, suggesting a chaperone function similar to that of calnexin | journal = The Journal of Biological Chemistry | volume = 271 | issue = 1 | pages = 97–103  | date = Jan 1996 | pmid = 8550632 | doi = 10.1074/jbc.271.1.97 | doi-access = free }}
* {{cite journal | vauthors = Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, Birkenbach M | title = A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes | journal = Journal of Virology | volume = 70 | issue = 2 | pages = 1143–53  | date = Feb 1996 | pmid = 8551575 | pmc = 189923 | doi =  10.1128/JVI.70.2.1143-1153.1996}}
* {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13  | date = Apr 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
* {{cite journal | vauthors = van Leeuwen JE, Kearse KP | title = Calnexin associates exclusively with individual CD3 delta and T cell antigen receptor (TCR) alpha proteins containing incompletely trimmed glycans that are not assembled into multisubunit TCR complexes | journal = The Journal of Biological Chemistry | volume = 271 | issue = 16 | pages = 9660–5  | date = Apr 1996 | pmid = 8621641 | doi = 10.1074/jbc.271.16.9660 | doi-access = free }}
* {{cite journal | vauthors = Oliver JD, Hresko RC, Mueckler M, High S | title = The glut 1 glucose transporter interacts with calnexin and calreticulin | journal = The Journal of Biological Chemistry | volume = 271 | issue = 23 | pages = 13691–6  | date = Jun 1996 | pmid = 8662691 | doi = 10.1074/jbc.271.23.13691 | doi-access = free }}
* {{cite journal | vauthors = Li Y, Bergeron JJ, Luo L, Ou WJ, Thomas DY, Kang CY | title = Effects of inefficient cleavage of the signal sequence of HIV-1 gp 120 on its association with calnexin, folding, and intracellular transport | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 18 | pages = 9606–11  | date = Sep 1996 | pmid = 8790377 | pmc = 38475 | doi = 10.1073/pnas.93.18.9606 | bibcode = 1996PNAS...93.9606L | doi-access = free }}
* {{cite journal | vauthors = Trombetta ES, Simons JF, Helenius A | title = Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound noncatalytic HDEL-containing subunit | journal = The Journal of Biological Chemistry | volume = 271 | issue = 44 | pages = 27509–16  | date = Nov 1996 | pmid = 8910335 | doi = 10.1074/jbc.271.44.27509 | doi-access = free }}
* {{cite journal | vauthors = Tatu U, Helenius A | title = Interactions between newly synthesized glycoproteins, calnexin and a network of resident chaperones in the endoplasmic reticulum | journal = The Journal of Cell Biology | volume = 136 | issue = 3 | pages = 555–65  | date = Feb 1997 | pmid = 9024687 | pmc = 2134297 | doi = 10.1083/jcb.136.3.555 }}
* {{cite journal | vauthors = Wiest DL, Bhandoola A, Punt J, Kreibich G, McKean D, Singer A | title = Incomplete endoplasmic reticulum (ER) retention in immature thymocytes as revealed by surface expression of "ER-resident" molecular chaperones | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 5 | pages = 1884–9  | date = Mar 1997 | pmid = 9050874 | pmc = 20012 | doi = 10.1073/pnas.94.5.1884 | bibcode = 1997PNAS...94.1884W | doi-access = free }}
* {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8  | date = Apr 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
{{refend}}
{{PDB Gallery|geneid=821}}
{{Calcium-binding proteins}}
{{Lectins}}
{{Membrane proteins}}
[[Category:Integral membrane proteins]]
[[Category:C-type lectins]]
[[Category:Molecular chaperones]]