The interleukin-like epithelial-mesenchymal transition inducer ILEI exhibits a non-interleukin-like fold and is active as a domain-swapped dimer
| Autor: | Patrik Johansson, Elisabeth Ax, Ann-Christin Nyström, Joachim Maier, Lovisa Holmberg Schiavone, Anna Jansson, Agnes Csiszar |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation Protein subunit Dimer Recombinant Fusion Proteins Cell Crystallography X-Ray Biochemistry 03 medical and health sciences chemistry.chemical_compound Mice Protein structure Cell Movement medicine Animals Humans Point Mutation Protein Interaction Domains and Motifs Epithelial–mesenchymal transition Cysteine Receptor Molecular Biology Cell Line Transformed Chemistry Protein Stability Interleukins Interleukin Molecular Bases of Disease Cell Biology Peptide Fragments Cell biology Neoplasm Proteins 030104 developmental biology medicine.anatomical_structure Amino Acid Substitution Tumor progression Structural Homology Protein Cystine Cytokines Dimerization |
| Zdroj: | The Journal of biological chemistry. 292(37) |
| ISSN: | 1083-351X |
| Popis: | Production and secretion of pro-metastatic proteins is a feature of many tumor cells. The FAM3C interleukin-like epithelial-to-mesenchymal-transition (EMT) inducer (ILEI) has been shown to be strongly up-regulated in several cancers and to be essential for tumor formation and metastasis in epithelial cells, correlating with a significant decrease in overall survival in colon and breast cancer patients. ILEI has been seen to interact with the γ-secretase presenilin 1 subunit (PS1). However, not much is known about the mechanism-of-action or the detailed ILEI structure. We present here the crystal structures of FAM3C ILEI and show that it exists as monomers but also as covalent dimers. The observed ILEI β-β-α fold confirmed previous indications that the FAM3C proteins do not form classical four-helix-bundle structures as was initially predicted. This provides the first experimental evidence that the interleukin-like EMT inducers are not evolutionarily related to the interleukins. However, more surprisingly, the ILEI dimer structure was found to feature a trans-linked domain swap, converting an intramolecular disulfide to intermolecular. Interestingly, dimeric but not monomeric ILEI was subsequently found to cause a dose-dependent increase in EpRas cell invasiveness comparable with TGF-β, indicating that the dimer might be the active ILEI species. This is in line with a parallel study showing that covalent oligomerization of ILEI is essential for EMT and tumor progression in vivo. The structures and the activity data give some first insight into the relationship between dimerization and ILEI function as well as indicate an intriguing link between ILEI, the PS1-protease, TGF-β, and the TGF-β receptor 1. |
| Databáze: | OpenAIRE |
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