Summary

Calnexin and Calreticulin are two chaperons in the Endoplasmic Reticulum, and they mediate the folding of all the proteins in the secretory pathway.

Proteins in the secretory pathway are synthesized by a ribosome attached to the ER membrane and immediately imported inside the ER. The folding of these protein happens in the ER, and a key signal in this process are the glycans attached co-translationally to the protein.

Calnexin is a type I transmembrane protein [1], while Calreticulin is soluble.

Disease relevance of CANX

• Our data show that the major degradation pathway of the cystic fibrosis transmembrane conductance regulator (CFTR) with F508del (the most frequent mutation found in patients with the genetic disease cystic fibrosis) from the ER is independent of calnexin [2].
• Nonglycosylated HIV envelope protein was not associated with calreticulin, suggesting a requirement for N-linked oligosaccharides on newly synthesized proteins as has been reported for calnexin [3].
• Roles of calreticulin and calnexin during mucin synthesis in LS180 and HT29/A1 human colonic adenocarcinoma cells [4].
• Metastatic melanoma lesions exhibited significant downregulation of calnexin as compared to primary melanoma lesions [5].
• It affected, however, the post-translational phases of oxidative influenza virus hemagglutinin (HA) folding, resulting in significant loss of folding efficiency for this obligate calnexin substrate [6].

Psychiatry related information on CANX

• The purpose was to determine whether obsessive-compulsive disorder (OC) is associated with a distinctive pattern of somatosensory evoked potential (SEP) measurements, based on amplitudes of the N60 (negativity 60 msec poststimulus), P90, and N130 peaks [7].

High impact information on CANX

• Further deglucosylation of the oligosaccharides by glucosidase II liberates glycoproteins from their calnexin/calreticulin anchors [8].
• Calnexin, an endoplasmic reticulum transmembrane protein, represents a new type of molecular chaperone that selectively associates in a transient fashion with newly synthesized monomeric glycoproteins in HepG2 cells [9].
• At least two main chaperone classes, BiP and calnexin/calreticulin, are active in ER quality control [10].
• More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle [11].
• Consistent with a requirement for multiple glycans to activate GII, pancreatic RNase in live cells needed more than one glycan to enter the Cnx/Crt cycle [11].

Chemical compound and disease context of CANX

• Calreticulin interacts with newly synthesized human immunodeficiency virus type 1 envelope glycoprotein, suggesting a chaperone function similar to that of calnexin [3].
• The present review summarizes the results of a legume lectin study as well as those obtained from a similar analysis carried out here on the animal lectins, namely galectins, pentraxins, calnexin, calreticulin and rhesus rotavirus Vp4 sialic-acid-binding domain [12].
• To analyze the role of glucose trimming and reglucosylation in the binding of substrate proteins to calnexin in the endoplasmic reticulum (ER) of living cells, we made use of the thermosensitive vesicular stomatitis virus tsO45 glycoprotein (G protein) [13].
• Here we show that in stably transfected hepatoma cells the additional processing of asparagine-linked oligosaccharides by endoplasmic reticulum mannosidase II partitions variant PI Z away from the conventional disposal mechanism in response to an arrested posttranslational interaction with calnexin [14].
• Disruption of the CA-CypA interaction, either by the competitive inhibitor cyclosporine (CsA) or by mutation of CA residue G89 or P90, suggested that producer cell CypA was required for full virion infectivity [15].

Biological context of CANX

• Folding of insulin receptor monomers is facilitated by the molecular chaperones calnexin and calreticulin and impaired by rapid dimerization [16].
• Participation of the endoplasmic reticulum chaperone calnexin (p88, IP90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator [17].
• The in vivo binding kinetics of calnexin and calreticulin to gp160 were very similar [3].
• Calnexin had access to novel N-glycosylated sites created in other extracytosolic loops in AE1 by site-directed or insertional mutagenesis [18].
• We found that calnexin-deficient cells are relatively resistant to ER stress-induced apoptosis [19].

Anatomical context of CANX

• In a beta2-microglobulin (beta2m)-negative mouse cell line, S3, ER-60-calnexin-heavy chain complexes are shown to bind to TAP, suggesting that beta2m is not required for the association of MHC class I heavy chains with TAP [20].
• Structural fidelity is monitored by endoplasmic reticulum (ER) quality control involving the molecular chaperone calnexin [2].
• However, in a T cell line that cannot assemble a complete T cell receptor because it lacks the alpha subunit, the unassembled T cell receptor beta chains, which are retained in the ER, remain associated with IP90 throughout a prolonged chase time period [21].
• Calnexin interaction with N-glycosylation mutants of a polytopic membrane glycoprotein, the human erythrocyte anion exchanger 1 (band 3) [18].
• An association of calnexin with truncated versions of N-glycosylated AE1 was detected after release of the nascent chains from ribosomes with puromycin [18].

Associations of CANX with chemical compounds

• An inhibitor of glucose trimming, castanospermine (CST), abolished binding to Cnx/Crt but also unexpectedly accelerated receptor homodimerization resulting in misfolded oligomeric proreceptors whose processing was delayed and cell surface expression was also decreased by approximately 30% [16].
• The glut 1 glucose transporter interacts with calnexin and calreticulin [22].
• Based upon coimmunoprecipitation and cosedimentation through glycerol density gradients, newly synthesized wild-type and delta F508 mutant CFTRs associated specifically with calnexin, the calcium-binding transmembrane chaperone of the ER [17].
• Ca(2+) homeostasis and ER morphology were unaffected by the lack of calnexin, but ER stress-induced Bap31 cleavage was significantly inhibited [19].
• RESULTS: Calreticulin and calsequestrin (the two major calcium storage proteins of somatic cells), two types of calcium release receptors, the inositol trisphosphate and ryanodine receptors (InsP(3)R-2, RyRs-1,2,3), and the molecular chaperone, calnexin, were identified in all investigated cell types [23].
• We show that calnexin interacts with the receptors via two distinct mechanisms, glycan-dependent and glycan-independent, which may underlie the multiple effects (ER retention and surface trafficking) of calnexin on receptor expression [24].

Physical interactions of CANX

• Immunoprecipitation experiments revealed that Bap31 forms complexes with calnexin, which may play a role in apoptosis [19].
• In this general way, CRT shares certain functional properties with the structurally homologous transmembrane calcium-binding endoplasmic reticulum protein calnexin [25].
• Calnexin Delta 185-520 interacted with CFTR directly, and was secreted into the extracellular compartment over time [26].
• Conditions that induce the calnexin "polypeptide-binding" conformation also induce self-association of calnexin if the concentration is sufficiently high; however, calnexin dimerization/oligomerization per se is not essential for polypeptide substrate binding [27].
• Calnexin and other factors that alter translocation affect the rapid binding of ubiquitin to apoB in the Sec61 complex [28].

Co-localisations of CANX

• Confocal microscopy with folate-deprived cells revealed that cytoplasmic BCRP colocalized with calnexin, an established endoplasmic reticulum resident [29].

Regulatory relationships of CANX

• The results suggest that calnexin may not play a role in the initiation of the ER stress but that the protein has an effect on later apoptotic events via its influence on Bap31 function [19].
• In vitro, the presence of calnexin-specific oligosaccharides inhibited the formation of calnexin dimers and higher order structures [27].
• The p90 mdm-2 protein could regulate p53 activity in the late G1 phase of the cell cycle [30].
• We show that the alpha-1,2-glucosidase inhibitor miglustat (N-butyldeoxynojirimycin, NB-DNJ) prevents delF508-CFTR/calnexin interaction and restores cAMP-activated chloride current in epithelial CF cells [31].
• Calnexin influences folding of human class I histocompatibility proteins but not their assembly with beta 2-microglobulin [32].

Other interactions of CANX

• Together, these studies demonstrate a chaperone function for Cnx/Crt in HIR folding in vivo and also provide evidence that folding efficiency and homodimerization are counterbalanced [16].
• A few of the positionally mapped genes in the 5q35 region that may potentially be involved in the etiology of this condition are CANX, FGFR4, HK3, and hnRPH1 [33].
• Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin [2].
• The formation of at least one of the disulfide bonds in the CD1d heavy chain is coupled to its glucose trimming-dependent association with ERp57, calnexin, and calreticulin [34].
• The results show that the interaction of calnexin with the polytopic membrane glycoprotein AE1 was dependent on the presence but not the location of the oligosaccharide [18].

Analytical, diagnostic and therapeutic context of CANX

• Following immunoprecipitation with an anticalnexin antiserum, a cross-linker-independent association was observed between GT155 and calnexin [22].
• In the present study, we compared melanoma lesions representing different stages of tumor progression with regard to the expression of calnexin and calreticulin in tumor cells by means of immunohistochemistry [5].
• Dissection of the degradation process revealed that upon release from calnexin, extensively oxidized BACE457 transiently entered in disulfide-bonded complexes associated with the lumenal chaperones BiP and protein disulfide isomerase (PDI) before unfolding and dislocation into the cytosol for degradation [35].
• In Calu-3 airway cells, immunofluorescence colocalized Csp with calnexin in the endoplasmic reticulum and with CFTR at the apical membrane domain [36].
• By cell fractionation, surface rTPO fractionated distinctly from internal pools of TPO (that co-fractionate with calnexin), yet surface TPO molecules remained endoglycosidase H (endo H)-sensitive [37].

References