CANX

CANX Full Name

calnexin

CANX Introduction

CANX (calnexin) is a type I integral membrane protein located in the endoplasmic reticulum (ER) that functions as a major molecular chaperone and lectin. The gene encoding CANX is located on human chromosome 5q35.3 and produces a protein of approximately 573 amino acids with a molecular weight of about 67 kDa. Calnexin is ubiquitously expressed in all nucleated cells and plays a critical role in the quality control of newly synthesized glycoproteins. It specifically recognizes monoglucosylated N‑linked glycans on folding intermediates, thereby facilitating proper protein folding, preventing aggregation, and retaining misfolded proteins in the ER. Calnexin is essential for the correct maturation of many secretory and membrane proteins, including immune receptors, ion channels, and extracellular matrix components. Its homolog in the lumen of the ER is calreticulin (CALR), which shares functional similarities but is soluble.

Figure 1. Strcuture of CANX.

Calnexin in Immune Function and Disease

Calnexin is essential for the proper folding and assembly of major histocompatibility complex (MHC) class I molecules, which present peptide antigens to cytotoxic T lymphocytes. In the ER, calnexin binds to the MHC class I heavy chain, stabilizing it until β₂‑microglobulin associates and the peptide‑loading complex is assembled. This function is critical for adaptive immunity; calnexin‑deficient cells exhibit reduced surface expression of MHC class I and impaired antigen presentation. Calnexin also participates in the folding of integrins, T‑cell receptors, and Toll‑like receptors. Beyond immunity, calnexin mutations or dysregulation have been linked to several human diseases. Loss‑of‑function mutations in CANX cause an autosomal recessive disorder called congenital dyserythropoietic anemia type II (CDA II) , characterized by ineffective erythropoiesis, hemolytic anemia, and abnormal multinucleated erythroblasts. Calnexin deficiency leads to misfolding of erythroid‑specific membrane proteins, resulting in premature erythroblast death. Additionally, calnexin is implicated in neurodegenerative diseases such as Parkinson's and Alzheimer's, where ER stress and protein misfolding play central roles.

Role in ER Glycoprotein Quality Control
Calnexin is a key component of the calnexin/calreticulin cycle, a specialized quality control system for N‑linked glycoproteins. As newly synthesized polypeptides enter the ER, they are co‑translationally glycosylated with a pre‑assembled oligosaccharide (Glc₃Man₉GlcNAc₂). The terminal glucose residues are sequentially trimmed by glucosidases I and II, producing a monoglucosylated intermediate (Glc₁Man₉GlcNAc₂) that is specifically recognized by calnexin. Binding of calnexin to the monoglucosylated glycan retains the folding protein in the ER and prevents premature export. Calnexin also interacts with the polypeptide backbone of the folding protein, and its P‑domain recruits ERp57, which catalyzes the formation and isomerization of disulfide bonds. Once the protein folds correctly, the remaining glucose is removed by glucosidase II, releasing it from calnexin. If the protein is still incompletely folded, UDP‑glucose:glycoprotein glucosyltransferase (UGGT) re‑glucosylates the glycan, allowing another round of calnexin binding. Misfolded proteins are eventually targeted for ER‑associated degradation (ERAD).

Alternate Names for CANX

CANX; calnexin; CNX; P90; IP90; major histocompatibility complex class I antigen-binding protein p88;