Calnexin

Calnexin is a type I integral membrane chaperone of the endoplasmic reticulum (ER) in eukaryotic cells and a central component of the ER folding and quality-control system. It has a single transmembrane domain that anchors it in the ER membrane, with a large luminal domain that acts as a lectin-like chaperone. Calnexin is closely related to its soluble partner calreticulin and is part of the calnexin/calreticulin cycle that assists the folding of N-linked glycoproteins.

The primary function of calnexin is to bind newly synthesized glycoproteins bearing monoglucosylated N-linked glycans. By recognizing these glycan structures, calnexin retains folding intermediates in the ER and coordinates their maturation. It forms a functional complex with the thiol-disulfide isomerase ERp57, which helps establish correct disulfide bonds in client proteins. Calnexin also interacts with enzymes of N-glycan processing and with UDP-glucose glycoprotein glucosyltransferase (UGGT), which reglucosylates misfolded glycoproteins to re-enter the calnexin/calreticulin cycle for another folding attempt.

In the normal folding pathway, glucose residues are progressively removed by glucosidases, allowing properly folded proteins to exit the ER and travel to the Golgi apparatus. If a glycoprotein remains misfolded, UGGT adds a glucose to its N-glycan, promoting another round of binding to calnexin (and calreticulin). Persistent misfolding can lead to retention in the ER and targeting for ER-associated degradation. Calnexin therefore contributes to protein quality control, ensuring that only correctly folded glycoproteins proceed along the secretory pathway.