CANX
Identifiers
AliasesCANX, CNX, IP90, P90, calnexin
External IDsOMIM: 114217 MGI: 88261 HomoloGene: 1324 GeneCards: CANX
Orthologs
SpeciesHumanMouse
Entrez

821

12330

Ensembl

ENSG00000283777
ENSG00000127022

ENSMUSG00000020368

UniProt

P27824

P35564

RefSeq (mRNA)

NM_001024649
NM_001746

NM_001110499
NM_001110500
NM_007597

RefSeq (protein)

NP_001103969
NP_001103970
NP_031623

Location (UCSC)Chr 5: 179.68 – 179.73 MbChr 11: 50.18 – 50.22 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Calnexin (CNX) is a 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 lumenal domain, a single transmembrane helix and a short (90 residues), acidic cytoplasmic tail.[5] In humans, calnexin is encoded by the gene CANX.[6]

Function

Calnexin is a 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.[7]

Calnexin binds only those N-glycoproteins that have GlcNAc2Man9Glc1 oligosaccharides.[8] These monoglucosylated oligosaccharides result from the trimming of two glucose residues by the sequential action of two glucosidases, 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.[9] The improperly-folded glycoprotein chain thus loiters in the ER and the expression of EDEM/Htm1p [10][11][12] which eventually sentences the underperforming glycoprotein to 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.[13]

Calnexin associates with the protein folding enzyme ERp57[14] 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.[15]

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[16] 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.[17]

The x-ray crystal structure of calnexin revealed a globular lectin domain and a long hydrophobic arm extending out.[18]

Cofactors

ATP and calcium ions are cofactors involved in substrate binding for calnexin.[19]

References

  1. 1 2 3 ENSG00000127022 GRCh38: Ensembl release 89: ENSG00000283777, ENSG00000127022 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020368 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Wada I, Rindress D, Cameron PH, Ou WJ, Doherty JJ 2nd, Louvard D, Bell AW, Dignard D, Thomas DY, Bergeron JJ (1991). "SSR alpha and associated calnexin are major calcium binding proteins of the endoplasmic reticulum membrane". J Biol Chem. 226 (29): 19599–610. doi:10.1016/S0021-9258(18)55036-5. PMID 1918067.
  6. ↑ Paskevicius T, Farraj RA, Michalak M, Agellon LB (2023). Lim D (ed.). "Calnexin, More Than Just a Molecular Chaperone". Cells. 12 (3): 403. doi:10.3390/cells12030403. PMC 9913998. PMID 36766745. Article No. 403.
  7. ↑ Ou WJ, Cameron PH, Thomas DY, Bergeron JJ (1993). "Association of folding intermediates of glycoproteins". Nature. 364 (644): 771–6. doi:10.1038/364771a0. PMID 8102790. S2CID 4340769.
  8. ↑ Hammond C, Braakman I, Helenius A (1984). "Role of N-linked oligosaccharide recognition, glucose trimming, and calnexin in glycoprotein folding and quality control". Proc Natl Acad Sci USA. 91 (3): 913–7. doi:10.1073/pnas.91.3.913. PMC 521423. PMID 8302866.
  9. ↑ Gañán S, Cazzulo JJ, Parodi AJ (1991). "A major proportion of N-glycoproteins are transiently glucosylated in the endoplasmic reticulum". Biochemistry. 30 (12): 3098–104. doi:10.1021/bi00226a017. PMID 1826090.
  10. ↑ Jacob CA, Bodmer D, Spirig U, Battig P, Marcil A, Dignard D, Bergeron JJ, Thomas DY, Aebi M (2001). "Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast". EMBO Rep. 2 (5): 423–30. doi:10.1093/embo-reports/kve089. PMC 1083883. PMID 11375935.
  11. ↑ Hosokawa N, Wada I, Hasegawa K, Yorihuzi T, Tremblay LO, Herscovics A, Nagata K (2001). "A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation". EMBO Rep. 2 (5): 415–2. doi:10.1093/embo-reports/kve084. PMC 1083879. PMID 11375934.
  12. ↑ Lee AH, Iwakoshi NN, Glimcher LH (2003). "XBP-1 regulates a subset of endoplasmic reticulum chaperone genes in the unfolded protein response". Mol Cell Biol. 23 (21): 5448–59. doi:10.1128/mcb.23.21.7448-7459.2003. PMC 207643. PMID 14559994.
  13. ↑ Quan EM, Kamiya D, Denic V, Weibezahn J, Kato K, Weissman JS (2008). "Defining the glycan destruction signal for endoplasmic reticulum-associated degradation". Mol Cell. 32 (6): 870–7. doi:10.1016/j.molcel.2008.11.017. PMC 2873636. PMID 19111666.
  14. ↑ Zapun A, Darby NJ, Tessier DC, Michalak M, Bergeron JJ, Thomas DY (1998). "Enhanced catalysis of ribonuclease B folding by the interaction of calnexin or calreticulin with ERp57". J Biol Chem. 273 (211): 6009–12. doi:10.1074/jbc.273.11.6009. PMID 9497314.
  15. ↑ Bergeron JJ, Brenner MB, Thomas DY, Williams DB (1994). "Calnexin: a membrane-bound chaperone of the endoplasmic reticulum". Trends Biochem Sci. 19 (3): 124–8. doi:10.1016/0968-0004(94)90205-4. PMID 8203019.
  16. ↑ Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, Thomas DY, Snipes GJ (2002). "Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for "gain-of-function" ER diseases". Proc Natl Acad Sci USA. 99 (15): 9852–7. Bibcode:2002PNAS...99.9852D. doi:10.1073/pnas.152621799. PMC 125041. PMID 12119418.
  17. ↑ Hara T, Hashimoto Y, Akuzawa T, Hirai R, Kobayashi H, Sato K (2014). "Rer1 and calnexin regulate endoplasmic reticulum retention of a peripheral myelin protein 22 mutant that causes type 1A Charcot-Marie-Tooth disease". Sci Rep. 4: 1–11. Bibcode:2014NatSR...4E6992H. doi:10.1038/srep06992. PMC 4227013. PMID 25385046.
  18. ↑ Schrag JD, Bergeron JJ, Li Y, Borisova S, Hahn M, Thomas DY, Cygler M (2001). "The structure of calnexin, an ER chaperone involved in quality control of protein folding". Mol Cell. 8 (3): 633–44. doi:10.1016/s1097-2765(01)00318-5. PMID 11583625.
  19. ↑ Ou WJ, Bergeron JJ, Li Y, Kang CY, Thomas DY (1995). "Conformational changes induced in the endoplasmic reticulum luminal domain of calnexin by Mg-ATP and Ca2+". J Biol Chem. 270 (30): 18051–9. doi:10.1074/jbc.270.30.18051. PMID 7629114.

Further reading

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