Disease relevance of Canx

• The lack of specificity for calnexin interaction reveals a novel role for calreticulin in OCAI albinism [1].
• We report here the molecular cloning and sequencing of SmIrV1 which contains a deduced amino acid sequence of 582 residues with similarity to three proteins: calnexin, calreticulin, and OvRal1, a surface antigen of the filarial nematode Onchocerca volvulus [2].
• Analyses with RT-PCR showed that TAP-1, TAP2, LMP-2, LMP7, LMP10, tapasin and calnexin mRNA specific for these genes was absent in metastases produced in immunocompetent mice [3].
• The molecular chaperone calnexin coimmunoprecipitates with secretion-incompetent variant null(Hong Kong) retained in stably transfected mouse hepatoma cells (Le, A., Steiner, J. L., Ferrell, G. A., Shaker, J. F., and Sifers, R. N. (1994) J. Biol. Chem. 269, 7514-7519) [4].
• We now report that a small fraction of calnexin is normally expressed on the surface of various cells such as mastocytoma cells, murine splenocytes, fibroblast cells, and human HeLa cells [5].

High impact information on Canx

• In human B-cell lines, however, class I/beta 2m dimers in the ER are physically associated with TAP molecules rather than calnexin [6].
• The molecular chaperone function of calnexin (IP90, p88), a 90-kilodalton protein that resides in the endoplasmic reticulum (ER), in the retention of representative chains of the TCR-CD3 complex in the ER was tested [7].
• Truncation mutants of calnexin, when transiently expressed in COS cells, were exported from the ER and either accumulated in the Golgi or progressed to the cell surface [7].
• The peptide-loading function was specific to calreticulin, since the defect in K42 could be rectified by transfection with calreticulin but not a soluble form of calnexin, which shares its lectin-like activity [8].
• The immunoglobulin alpha (Ig alpha)/Ig beta heterodimer was detected on the surface of mu-negative proB cell lines in association with calnexin [9].

Biological context of Canx

• Despite its profound involvement in protein folding, calnexin is not essential for mammalian-cell viability in vivo: calnexin gene knockout mice were carried to full term, although 50% died within 48 h and the majority of the remaining mice had to be sacrificed within 4 weeks, with only a very few mice surviving to 3 months [10].
• Therefore, the different topological environments of calnexin and calreticulin are important in determining their distinct substrate specificities [11].
• These results suggest that spermatogenic cell endoplasmic reticulum has a unique calcium binding protein, calnexin-t, which appears to be a calnexin variant [12].
• Co-immunoprecipitation and pulse-chase analyses revealed similar kinetics of apo(a) interaction with CNX and CRT, peaking 15-30 min after apo(a) synthesis [13].
• The gene for human calnexin is located on the distal end of the long arm of human chromosome 5, at 5q35 [14].

Anatomical context of Canx

• Calreticulin and calnexin are homologous lectins that serve as molecular chaperones for glycoproteins in the endoplasmic reticulum of eukaryotic cells [15].
• In Trembler-J (Tr-J) sciatic nerves, prolonged association of mutant PMP-22 with CNX is found (t(1/2) > 60 min) [16].
• Calnexin and calreticulin are homologous lectin chaperones that assist maturation of cellular and viral glycoproteins in the mammalian endoplasmic reticulum [17].
• Calnexin gene-deficient mice were smaller than their littermates and showed very obvious motor disorders, associated with a dramatic loss of large myelinated nerve fibers [10].
• To test the role of ER luminal environment in apoptosis, we generated HeLa cell lines inducible with respect to calreticulin and calnexin and investigated their sensitivity to drug-dependent apoptosis [18].

Associations of Canx with chemical compounds

• Although not fully interchangeable during assistance of glycoprotein folding, calreticulin and calnexin may work, independently, as efficient and crucial factors for retention in the ER of nonnative polypeptides [15].
• Notably, this glycan-independent interaction with calnexin significantly retards the degradation of misfolded PLP [19].
• Calnexin (Cnx), a type-1 integral transmembrane ER protein which is partially homologous to Crt but lacks the KDEL sequence, is not detected on the cell surface either [20].
• Functional relationship between calreticulin, calnexin, and the endoplasmic reticulum luminal domain of calnexin [11].
• Involvement of the chaperone protein calnexin and the acetylcholine receptor beta-subunit in the assembly and cell surface expression of the receptor [21].

Physical interactions of Canx

• Conversely, membrane-anchored calreticulin bound to a similar set of glycoproteins as calnexin [11].
• However, H2b, which will exit to the Golgi, dissociated from calnexin and remained bound for a longer period to ERp57, whereas the opposite was true for the endoplasmic reticulum-associated degradation substrate H2a that will go to the endoplasmic reticulum-derived quality control compartment [22].
• During the normal folding pathway, TRP-1 interacts with calnexin [23].
• SR-A interacts with calnexin and when the association is prevented changes in the recycling kinetics and rate of turnover of the receptor result, leading to enhanced cell surface expression [24].
• Lectin-deficient calnexin is capable of binding class I histocompatibility molecules in vivo and preventing their degradation [25].

Enzymatic interactions of Canx

• Furthermore, calnexin was cleaved in vitro by recombinant caspase-3 or caspase-7 [26].
• Class I histocompatibility molecule association with phosphorylated calnexin. Implications for rates of intracellular transport [27].

Regulatory relationships of Canx

• Calnexin is thought to retain free class I heavy chains and/or promote their folding and assembly with beta 2-microglobulin and peptide ligand [28].
• Upon persistent misfolding, tsO45 G was slowly released from calnexin and entered a second level of retention-based ER quality control by forming BiP/GRP78-associated disulfide-bonded aggregates [29].
• CD3 molecules are expressed on the surface of these cells in association with calnexin [30].

Other interactions of Canx

• Calreticulin associated more abundantly with orphan calnexin substrates only in infected cells and preferentially with polypeptides of viral origin, showing stronger dependence of model viral glycoproteins on endoplasmic reticulum lectins [17].
• In contrast, with the zwitterionic detergent CHAPS, non-raft residents such as calnexin and APP also buoyed [31].
• Calnexin-t (calmegin) is a male germ cell-specific variant of calnexin, a membrane bound-molecular chaperone in the endoplasmic reticulum (ER) [32].
• Class II histocompatibility molecules associate with calnexin during assembly in the endoplasmic reticulum [33].
• Specifically, calnexin associates in the ER with free Ii polypeptides and partially assembled wild-type class II complexes, including A alpha and/or A alpha Ii complexes, as well as with alpha beta dimers isolated from class II transport-defective cells [33].

Analytical, diagnostic and therapeutic context of Canx

• Molecular cloning and expression of SmIrV1, a Schistosoma mansoni antigen with similarity to calnexin, calreticulin, and OvRal1 [2].
• We have used a PCR strategy to identify the Schizosaccharomyces pombe calnexin homologue, cnx1+ [34].
• Confocal microscopy of HepG2 cells revealed that CEH immunoreactive material colocalized with calnexin, a marker of the endoplasmic reticulum [35].
• To test the relative importance of the lectin site compared with the polypeptide-binding site, we have generated six calnexin mutants defective in oligosaccharide binding using site-directed mutagenesis [25].
• In double-label immunofluorescence microscopy, a portion of the mutant CPE did not colocalize with calnexin, an endoplasmic reticulum marker, but was found in prohormone convertase 2-containing secretory granules, demonstrating that it had escaped degradation and arrived at a post-Golgi compartment [36].

References