Calnexin is a
chaperone, characterized by assisting
protein folding and quality control, ensuring that only properly folded and assembled proteins proceed further along the
secretory pathway. It specifically acts to retain unfolded or unassembled N-linked
glycoproteins in the ER. Calnexin binds only those
N-
glycoproteins that have GlcNAc2Man9Glc1
oligosaccharides. These monoglucosylated oligosaccharides result from the trimming of two glucose residues by the sequential action of two
glucosidases, I and II. Glucosidase II can also remove the third and last glucose residue. If the glycoprotein is not properly folded, an enzyme called
UGGT (for UDP-glucose:glycoprotein glucosyltransferase) will add the glucose residue back onto the oligosaccharide thus regenerating the glycoprotein's ability to bind to calnexin. The improperly-folded glycoprotein chain thus loiters in the ER and the expression of EDEM/Htm1p which eventually sentences the underperforming glycoprotein to
degradation by removing one of the nine
mannose residues. The mannose lectin Yos-9 (OS-9 in humans) marks and sorts misfolded glycoproteins for degradation. Yos-9 recognizes mannose residues exposed after α-mannosidase removal of an outer mannose of misfolded glycoproteins. Calnexin associates with the protein folding enzyme ERp57 to catalyze glycoprotein specific disulfide bond formation and also functions as a chaperone for the folding of
MHC class I α-chain in the membrane of the ER. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state. After the β2-microglobulin binds to the MHC class I peptide-loading complex (PLC), calreticulin and ERp57 take over the job of chaperoning the MHC class I protein while the tapasin links the complex to the
transporter associated with antigen processing (TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface. A prolonged association of calnexin with mutant misfolded
PMP22 known to cause
Charcot-Marie-Tooth Disease leads to the sequestration, degradation and inability of PMP22 to traffic to the
Schwann cell surface for
myelination. After repeated rounds of calnexin binding, mutant PMP22 is modified by
ubiquitin for degradation by the
proteasome as well as a Golgi to ER retrieval pathway to return any misfolded PMP22 that escaped from the ER to the Golgi apparatus. The x-ray crystal structure of calnexin revealed a globular lectin domain and a long hydrophobic arm extending out. == Cofactors ==