Function
AGR2_HUMAN
Originally discovered in Xenopus laevis as a cement gland differentiation regulator [1], (AGR2) in humans is a protein chaperone (chaperones) involved in proteostasis, mainly for proteins expressed in epithelial cells, such as in the esophagus or lungs[2]. 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 interactive model[3].
- an unfolded NH2 terminal sequence with a peptide signal from the first to the 21st amino acid.
- an active pseudo-thioredoxin domain (CXXS) from the .
Called “pseudo” because there is only one active cysteine residue ()
- a terminal COOH sequence with a KTEL motif from the
Moreover, this protein can be found as a monomer or a dimer, thanks to a specific motif which is EALYK between the . 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[4].
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 (ER-resident protein), 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[5], which catalyzes the formation and isomerization of disulfide bonds during protein folding[6]. This protein mainly allows the folding of cysteine-rich proteins, such as the protein coded by the gene MUC2 (6rbf), by forming disulfide bridges[7]. 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[8].
Disease
Different links between this protein and the appearance of some pathologies such as cancers or inflammatory diseases have been highlighted.
In fact, it has been possible to deduce that its involvement in proteostasis may play an important role in the development of tumors and more specifically in the multiplication of abnormal or mutated proteins in tumor cells.
This protein plays a role in hormone-dependent cancers such as breast and prostate cancer. Indeed, AGR2 is not constitutive and its expression is regulated by signals. In this regard, ARG2 expression is detected in women with breast cancer, and their prognosis is poor.
Furthermore, in a study on inflammatory diseases, it was found that a mutation on () (which is part of the CXXS domain) in AGR2 causes an alteration in the interactions with mucin proteins.
In this pathway, the overexpression of AGR2 can cause an overexpression of mucus which, in breast cancer, participates in the proliferation of cancer cells and metastasis.
The AGR2 protein can form complexes with Reptin (2cqa) which is recognized as an anti-oncogene. However, it binds more easily when the protein is in dimeric form. Thus, a mutation on () site, giving the protein a monomeric form, would reduce cancer repression by Reptin.
Finally, the expression of AGR2 in breast cancer patients confers chemoresistance to cancer cell growth inhibitors such as Tamoxifen, the mechanism is still unclear.[9]
3D Structures of anterior gradient protein
Updated on 02-October-2024
2lns - hAGR2 - human - NMR
2lnt - hAGR2 (mutant) - NMR
3ph9 - hAGR3
References
- ↑ Delom F, Mohtar MA, Hupp T, Fessart D. The anterior gradient-2 interactome. Am J Physiol Cell Physiol. 2020 Jan 1;318(1):C40-C47. doi:, 10.1152/ajpcell.00532.2018. Epub 2019 Oct 23. PMID:31644305 doi:http://dx.doi.org/10.1152/ajpcell.00532.2018
- ↑ Moidu NA, A Rahman NS, Syafruddin SE, Low TY, Mohtar MA. Secretion of pro-oncogenic AGR2 protein in cancer. Heliyon. 2020 Sep 23;6(9):e05000. doi: 10.1016/j.heliyon.2020.e05000. eCollection, 2020 Sep. PMID:33005802 doi:http://dx.doi.org/10.1016/j.heliyon.2020.e05000
- ↑ Moidu NA, A Rahman NS, Syafruddin SE, Low TY, Mohtar MA. Secretion of pro-oncogenic AGR2 protein in cancer. Heliyon. 2020 Sep 23;6(9):e05000. doi: 10.1016/j.heliyon.2020.e05000. eCollection, 2020 Sep. PMID:33005802 doi:http://dx.doi.org/10.1016/j.heliyon.2020.e05000
- ↑ Delom F, Mohtar MA, Hupp T, Fessart D. The anterior gradient-2 interactome. Am J Physiol Cell Physiol. 2020 Jan 1;318(1):C40-C47. doi:, 10.1152/ajpcell.00532.2018. Epub 2019 Oct 23. PMID:31644305 doi:http://dx.doi.org/10.1152/ajpcell.00532.2018
- ↑ Fomenko DE, Gladyshev VN. CxxS: fold-independent redox motif revealed by genome-wide searches for thiol/disulfide oxidoreductase function. Protein Sci. 2002 Oct;11(10):2285-96. doi: 10.1110/ps.0218302. PMID:12237451 doi:http://dx.doi.org/10.1110/ps.0218302
- ↑ Fomenko DE, Gladyshev VN. Identity and functions of CxxC-derived motifs. Biochemistry. 2003 Sep 30;42(38):11214-25. doi: 10.1021/bi034459s. PMID:14503871 doi:http://dx.doi.org/10.1021/bi034459s
- ↑ Moidu NA, A Rahman NS, Syafruddin SE, Low TY, Mohtar MA. Secretion of pro-oncogenic AGR2 protein in cancer. Heliyon. 2020 Sep 23;6(9):e05000. doi: 10.1016/j.heliyon.2020.e05000. eCollection, 2020 Sep. PMID:33005802 doi:http://dx.doi.org/10.1016/j.heliyon.2020.e05000
- ↑ Fessart D, Domblides C, Avril T, Eriksson LA, Begueret H, Pineau R, Malrieux C, Dugot-Senant N, Lucchesi C, Chevet E, Delom F. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties. Elife. 2016 May 30;5. doi: 10.7554/eLife.13887. PMID:27240165 doi:http://dx.doi.org/10.7554/eLife.13887
- ↑ Brychtova V, Mohtar A, Vojtesek B, Hupp TR. Mechanisms of anterior gradient-2 regulation and function in cancer. Semin Cancer Biol. 2015 Aug;33:16-24. doi: 10.1016/j.semcancer.2015.04.005. Epub , 2015 Apr 30. PMID:25937245 doi:http://dx.doi.org/10.1016/j.semcancer.2015.04.005
