Calnexin, Calreticulin, and ERp57: Teammates in Glycoprotein Folding

Abstract

In eukaryotic cells, the endoplasmic reticulum (ER) plays an essential role in the synthesis and maturation of a variety of important secretory and membrane proteins. For glycoproteins, the ER possesses a dedicated maturation system, which assists folding and ensures the quality of final products before ER release. Essential components of this system include the lectin chaperones calnexin (CNX) and calreticulin (CRT) and their associated co-chaperone ERp57, a glycoprotein specific thiol-disulfide oxidoreductase. The significance of this system is underscored by the fact that CNX and CRT interact with practically all glycoproteins investigated to date, and by the debilitating phenotypes revealed in knockout mice deficient in either gene. Compared to other important chaperone systems, such as the Hsp70s, Hsp90s and GroEL/GroES, the principles whereby this system works at the molecular level are relatively poorly understood. However, recent structural and biochemical data have provided important new insights into this chaperone system and present a solid basis for further mechanistic studies.

N-Linked Glycosylation Is Required for Nicotinic Receptor Assembly but Not for Subunit Associations with Calnexin

“…Our results with CN are at odds with other reports that found CAS significantly reduced the association of the ␣-subunit with CN (35). To block N-linked glycosylation of the AChR subunits using TUN, cells co-expressing each AChR 1, 3, 5, 7) or an HA-specific Ab (lanes 2, 4,6,8), and compared with each other (see TABLE ONE; n ϭ 5-7; Ϯ S.E. for each subunit).…”

“…Recent studies suggest that CN is part of a larger complex that contains other components such as the thiol oxidoreductase ERp57 (reviewed in Ref. 4). …”

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

“…CALR is known to be involved in the regulation of calcium uptake and release in the endoplasmic reticulum, 42 and acts as a chaperone, together with calnexin and ERp57, to form part of the regulatory machinery involved in the folding and quality control of newly synthesized glycoproteins. 43 Differences in cytosolic calcium mobilization have been reported with the 52 base pair deletion, 44 suggesting that this may be one mechanism by which mutant CALR exerts its effect, and expression of the mutant protein does appear to be particularly restricted to megakaryocytes on immunohistochemical evaluation of bone marrow specimens. 45 More recently, it has been shown that CALR mutations can impart TPO-independence in both cell lines 46,47 and retroviral mouse models, 48,49 in a MPL-and JAK2-dependent manner, mimicking the effect of activating MPL mutations.…”

A Novel Stress-induced EDEM Variant Regulating Endoplasmic Reticulum-associated Glycoprotein Degradation

“…Each of the sugar units composing the protein-bound glycan plays a role in the transfer of the branched glycan from the lipid donor in the ER membrane to nascent polypeptides, in mediating binding/release from ER resident lectins, and/or in determining the fate of the associated polypeptide chain (1). Glucose trimming by glucosidase I and glucosidase II and glucose re-addition by UDPglucose:glycoprotein glucosyltransferase (GT) allows nascent and newly synthesized proteins access to and cycling into a system of chaperones composed by the homologous lectins calnexin (Cnx) and calreticulin (Crt) and the associated oxidoreductase ERp57 (2)(3)(4)(5). Native proteins are transported along the secretory line to their destination, but a certain fraction of newly synthesized polypeptides will never make it into a native, export-competent structure.…”