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]

Quick Facts CANX, Identifiers ...

CANX
Identifiers
Aliases	CANX, CNX, IP90, P90, calnexin
External IDs	OMIM: 114217 MGI: 88261 HomoloGene: 1324 GeneCards: CANX
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q35.3 Start 179,678,628 bp[1] End 179,730,925 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 B1.3|11 30.46 cM Start 50,184,788 bp[2] End 50,216,500 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium islet of Langerhans Achilles tendon bone marrow cells thymus corpus callosum smooth muscle tissue sural nerve placenta body of pancreas Top expressed in medullary collecting duct paraventricular nucleus of hypothalamus primitive streak renal corpuscle lacrimal gland arcuate nucleus median eminence dorsomedial hypothalamic nucleus ventral tegmental area globus pallidus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding apolipoprotein binding unfolded protein binding metal ion binding ionotropic glutamate receptor binding carbohydrate binding RNA binding protein binding Cellular component cytoplasm integral component of membrane mitochondria-associated endoplasmic reticulum membrane rough endoplasmic reticulum ribosome endoplasmic reticulum lumen endoplasmic reticulum membrane membrane melanosome myelin sheath dendritic spine smooth endoplasmic reticulum axon neuronal cell body endoplasmic reticulum dendrite cytoplasm integral component of lumenal side of endoplasmic reticulum membrane extracellular exosome extracellular matrix protein-containing complex endoplasmic reticulum quality control compartment glutamatergic synapse integral component of postsynaptic membrane integral component of presynaptic active zone membrane Biological process antigen processing and presentation of exogenous peptide antigen via MHC class II antigen processing and presentation of peptide antigen via MHC class I human ageing protein folding in endoplasmic reticulum protein secretion clathrin-dependent endocytosis synaptic vesicle endocytosis protein folding chaperone-mediated protein folding interleukin-12-mediated signaling pathway interleukin-27-mediated signaling pathway interleukin-35-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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_001019820 NP_001737 NP_001350922 NP_001350923 NP_001350924 NP_001350925 NP_001350926 NP_001350927 NP_001350928 NP_001350929 NP_001350930 NP_001103969 NP_001103970 NP_031623 Location (UCSC) Chr 5: 179.68 – 179.73 Mb Chr 11: 50.18 – 50.22 Mb PubMed search [3] [4]
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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]

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