Anterior gradient protein
From Proteopedia
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== Anterior Gradient Protein 2 == | == Anterior Gradient Protein 2 == | ||
<StructureSection load='2LNS' size='350' side='right' caption='residues 41-175 of AGR2 in dimer form (PDB entry [[2lns]])' scene='87/872187/Agr2_full/1'> | <StructureSection load='2LNS' size='350' side='right' caption='residues 41-175 of AGR2 in dimer form (PDB entry [[2lns]])' scene='87/872187/Agr2_full/1'> | ||
| + | __TOC__ | ||
| + | ==Function== | ||
[https://www.uniprot.org/uniprot/AGR2_HUMAN AGR2_HUMAN] | [https://www.uniprot.org/uniprot/AGR2_HUMAN AGR2_HUMAN] | ||
Originally discovered in Xenopus laevis as a cement gland differentiation regulator <ref>PMID: 31644305</ref>, <scene name='87/872187/Agr2_full/1'>Anterior Gradient Protein 2</scene> (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<ref>PMID:33005802</ref>. AGR2, composed of 175 amino acids, belongs to the protein disulfide isomerase family ([https://www.uniprot.org/uniprot/P07237 PDI]). | Originally discovered in Xenopus laevis as a cement gland differentiation regulator <ref>PMID: 31644305</ref>, <scene name='87/872187/Agr2_full/1'>Anterior Gradient Protein 2</scene> (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<ref>PMID:33005802</ref>. AGR2, composed of 175 amino acids, belongs to the protein disulfide isomerase family ([https://www.uniprot.org/uniprot/P07237 PDI]). | ||
== Structural highlights == | == Structural highlights == | ||
This protein contains various remarkable domains which can be visualized in the interactive model<ref>PMID:33005802</ref>. | This protein contains various remarkable domains which can be visualized in the interactive model<ref>PMID:33005802</ref>. | ||
| - | + | '''- 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 <scene name='87/872187/Agr2_cxxs/2'>81st to the 84th amino acid</scene>. | |
Called “pseudo” because there is only one active cysteine residue (<scene name='87/872187/Agr2_c81/2'>C81</scene>) | Called “pseudo” because there is only one active cysteine residue (<scene name='87/872187/Agr2_c81/2'>C81</scene>) | ||
| - | + | ''' - a terminal COOH sequence with a KTEL motif from the <scene name='87/872187/Agr2_cter/1'>172nd to the last amino acid.</scene>''''' | |
Moreover, this protein can be found as a monomer or a dimer, thanks to a specific motif which is '''EALYK''' between the <scene name='87/872187/Agr2_dim/1'>60th and the 64th amino acids</scene>. 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<ref>PMID: 31644305</ref>. | Moreover, this protein can be found as a monomer or a dimer, thanks to a specific motif which is '''EALYK''' between the <scene name='87/872187/Agr2_dim/1'>60th and the 64th amino acids</scene>. 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<ref>PMID: 31644305</ref>. | ||
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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. | 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. | 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 (<scene name='87/872187/Agr2_c81/2'>C81</scene>) (which is part of the CXXS domain) in AGR2 causes an alteration in the interactions with mucin proteins. | + | Furthermore, in a study on inflammatory diseases, it was found that a mutation on (<scene name='87/872187/Agr2_c81/2'>C81</scene>) (which is part of the CXXS domain) in AGR2 causes an alteration in the interactions with [https://onlinelibrary.wiley.com/doi/abs/10.1111/imr.12182 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. | 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 [https://www.uniprot.org/uniprot/Q9Y230 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 (<scene name='87/872187/Agr2_e60/2'>E60</scene>) site, giving the protein a monomeric form, would reduce cancer repression by Reptin. | The AGR2 protein can form complexes with [https://www.uniprot.org/uniprot/Q9Y230 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 (<scene name='87/872187/Agr2_e60/2'>E60</scene>) 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.<ref>PMID: 25937245</ref> | Finally, the expression of AGR2 in breast cancer patients confers chemoresistance to cancer cell growth inhibitors such as Tamoxifen, the mechanism is still unclear.<ref>PMID: 25937245</ref> | ||
| - | </StructureSection> | ||
| + | == 3D Structures of anterior gradient protein == | ||
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| + | Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | ||
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| + | [[2lns]] - hAGR2 - human - NMR<br /> | ||
| + | [[2lnt]] - hAGR2 (mutant) - NMR<br /> | ||
| + | [[3ph9]] - hAGR3<br /> | ||
== References == | == References == | ||
<references/> | <references/> | ||
| + | </StructureSection> | ||
| + | [[Category:Topic Page]] | ||
Current revision
Anterior Gradient Protein 2
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