Anterior gradient protein

Originally discovered in Xenopus laevis as a cement gland differentiation regulator, (AGR2) in humans is a protein chaperone involved in proteostasis, mainly for proteins expressed in epithelial cells, such as in the esophagus or lungs. AGR2, composed of 175 amino acids, belongs to the protein disulfide isomerase family (PDI).

Structural highlights

This protein contains various remarkable domains which can be visualized in the figure.

 - an unfolded NH2 terminal sequence with a peptide signal from the first to the 21st amino acid 

 - an active pseudo-thioredoxin domain () from the 81st to the 84th amino acid. Called “pseudo” because there is only one active cysteine residue (C81)

 - a terminal COOH sequence with a KTEL motif from the 172nd to the last  

Moreover, this protein can be found as a monomer or a dimer, thanks to a specific motif which is EALYK between the 60th and the 64th amino acids. There are intermolecular salt bridges involving E60 and K64, in order to fix the second monomer. The CXXS domain is on the opposite side to avoid any disulfide exchange. Nevertheless, the dimeric structure is oxidation-dependent which means that C81 is necessary.

Functions

AGR2 does not have the same roles if it is found in the extracellular matrix, or the intracellular milieu. According to the patterns found in N-ter and C-ter it seems obvious that AGR2 is a protein intended to reside in the ER, so inside the cells. Indeed, N-ter sequence directs the import of AGR2 into the ER and is responsible for the cell adhesion properties of AGR2, and the C-ter sequence prevents the AGR2 from being exported out of the ER. Within the latter, AGR2 allows the folding of nascent proteins in the ER, in order to mature them, through its CXXS domain, which catalyzes the formation and isomerization of disulfide bonds during protein folding. This protein mainly allows the folding of cysteine-rich proteins, such as the protein coded by the gene MUC2, by forming disulfide bridges. However, it happens that AGR2 is found outside the ER despite its function as a disulfide isomerase and its C-ter sequence, the reason remains unclear. In a cancerous medium such as serum or urine, extracellular AGR2 is often found in large quantities.

Disease