5LC2

Xray structure of human FAM3C ILEI monomer

5LC2 の概要

• エントリーDOI: 10.2210/pdb5lc2/pdb
• 分子名称: Protein FAM3C (2 entities in total)
• 機能のキーワード: signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 45325.92

構造登録者

Johansson, P.,Jansson, A. (登録日: 2016-06-19, 公開日: 2017-08-02, 最終更新日: 2024-11-20)

主引用文献

Jansson, A.M.,Csiszar, A.,Maier, J.,Nystrom, A.C.,Ax, E.,Johansson, P.,Schiavone, L.H.
The interleukin-like epithelial-mesenchymal transition inducer ILEI exhibits a non-interleukin-like fold and is active as a domain-swapped dimer.
J. Biol. Chem., 292:15501-15511, 2017

PubMed Abstract: 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 -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 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.

PubMed: 28751379
DOI: 10.1074/jbc.M117.782904

実験手法

X-RAY DIFFRACTION (1.8 Å)