8.A.165. The Calnexin (Calnexin) Family
The endoplasmic reticulum (ER) is the major folding compartment for secreted and membrane proteins in eukaryotes and is the site of a specific chaperone system, the calnexin cycle, for folding N-glycosylated proteins. Structures of components of the calnexin cycle have revealed quality control mechanisms and protein folding pathways in the ER. In the calnexin cycle, proteins carrying monoglucosylated glycans bind to the lectin chaperones calnexin and calreticulin, which recruit a variety of function-specific chaperones to mediate protein disulfide formation, proline isomerization, and general protein folding. Upon trimming by glucosidase II, the glycan without an inner glucose residue is no longer able to bind to the lectin chaperones. For proteins that have not yet folded properly, the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) acts as a checkpoint by adding a glucose back to the N-glycan. This allows the misfolded proteins to re-associate with calnexin and calreticulin for additional rounds of chaperone-mediated refolding and prevents them from exiting the ERs. Lee et al. 2020 reviewed progress in structural studies of the calnexin cycle, which revealed common features of how lectin chaperones recruit function-specific chaperones and how UGGT recognizes misfolded proteins. Calnexin aids in the folding of transport proteins (see TC#s 2.A.22.2.10 and 9.A.49.1.2 and 3).
Calreticulin is a sugar-binding protein chaparone (a lectin-like chaperone) that functions in peptide-loading to the major histocompatibility complex encoded class I (MHC-I) molecules (Margulies et al. 2020). The uterine sacroplasmic reticulum (SR) takes up and stores calcium [Ca], using the SERCA ATPase and the Ca-buffering proteins, calsequestrin and calreticulin. This stored Ca can be released via IP(3)-gated Ca channels (Noble et al. 2009), so calreticulin serves as an intermediate between the SERCA ATPase and Ca channels such as IP930-gated channels. The pre-apoptotic translocation of intracellular calreticulin (endo-CRT) to the plasma membrane surface (ecto-CRT) is critical for the recognition and engulfment of dying tumor cells by dendritic cells (Obeid et al. 2007). The ER protein CANX (calnexin)-mediates autophagy and protects against alzheimer disease (AD) (Shen et al. 2025).
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Calnexin (CANX) of 627 aas and 2 TMSs, one at the N-terminus, and one near the C-terminus. It is a calcium-binding protein that interacts with newly synthesized glycoproteins in the endoplasmic reticulum (ER). It may act in assisting protein assembly and/or in the retention within the ER of unassembled protein subunits. It seems to play a major role in the quality control apparatus of the ER by the retention of incorrectly folded proteins. It is associated with partial T-cell antigen receptor complexes that escape the ER of immature thymocytes, and may function as a signaling complex regulating thymocyte maturation. Additionally it may play a role in receptor-mediated endocytosis at the synapse. (See family description for more details). Calnexin aids in the folding of transport proteins (see TC#s 2.A.22.2.10 and 9.A.49.1.2 and 3) and in the proper insertion of ER membrane glycoproteins via the general secretory pathway (TC# 3.A.5) (Lee et al. 2020). The ER protein CANX (calnexin)-mediates autophagy and protects against alzheimer disease (AD) (Shen et al. 2025).
CONX of Homo sapiens
Calreticulin (CRT) of 417 aas and one N-terminal TMS. Calreticulin is a sugar-binding protein chaparone (a lectin-like chaperone) that functions in peptide-loading to the major histocompatibility complex encoded class I (MHC-I) molecules (Margulies et al. 2020). The uterine sacroplasmic reticulum (SR) takes up and stores calcium [Ca], using the SERCA ATPase and the Ca-buffering proteins, calsequestrin and calreticulin. This stored Ca can be released via IP(3)-gated Ca channels (Noble et al. 2009), so calreticulin serves as an intermediate between the SERCA ATPase and Ca channels such as IP930-gated channels. The pre-apoptotic translocation of intracellular calreticulin (endo-CRT) to the plasma membrane surface (ecto-CRT) is critical for the recognition and engulfment of dying tumor cells by dendritic cells (Obeid et al. 2007).
CRT of Homo sapiens
Calreticulin family protein of 437 aas and 4 TMSs, three N-terminal and one C-terminal. The similarity with other members of the family are in the central hydrophilc region of the protein.
Calreticulin-like protein of Toxoplasma gondii
Uncharacterized protein of 382 aas and at least two TMSs, N- and C-terminal.
UP of Candida glabrata
Uncharacterized protein of 382 aas and 0 TM
UP of Prunus mume
Calreticulin family protein of 682 aas and 3 TMSs, 1 (or 2) N-terminal and 2 C-terminal.
Calreticulin family protein of Cystoisospora suis
Sphingomyelin phosphodiesterase 2 of 563 aas and 3 TMSs, one N-terminal and two at residues 320 - 365.
SPD2 of Trichonephila clavipes