5lc4

From Proteopedia

Xray structure of mouse FAM3C ILEI dimer

Structural highlights

5lc4 is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.84Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FAM3C_MOUSE May be involved in retinal laminar formation. Promotes epithelial to mesenchymal transition.^[1] ^[2] ^[3]

Publication Abstract from PubMed

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 gamma-secretase presenilin 1 subunit (PS1). However, not much is known about the mechanism-of-action or the detailed ILEI structure. We here present the crystal structures of FAM3C ILEI and show that it exists as monomers but also as covalent dimers. The observed ILEI beta-beta-alpha 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 to TGF-beta, 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 gives some first insight into the relationship between dimerization and ILEI function as well as indicate an intriguing link between ILEI, the PS1-protease, TGF-beta and the TGF-beta receptor 1.

The interleukin-like epithelial-mesenchymal transition inducer ILEI exhibits a non-interleukin-like fold and is active as a domain-swapped dimer.,Jansson AM, Csiszar A, Maier J, Nystrom AC, Ax E, Johansson P, Holmberg Schiavone L J Biol Chem. 2017 Jul 27. pii: jbc.M117.782904. doi: 10.1074/jbc.M117.782904. PMID:28751379^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Waerner T, Alacakaptan M, Tamir I, Oberauer R, Gal A, Brabletz T, Schreiber M, Jechlinger M, Beug H. ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell. 2006 Sep;10(3):227-39. PMID:16959614 doi:http://dx.doi.org/10.1016/j.ccr.2006.07.020
↑ Lahsnig C, Mikula M, Petz M, Zulehner G, Schneller D, van Zijl F, Huber H, Csiszar A, Beug H, Mikulits W. ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression. Oncogene. 2009 Feb 5;28(5):638-50. doi: 10.1038/onc.2008.418. Epub 2008 Nov 17. PMID:19015638 doi:http://dx.doi.org/10.1038/onc.2008.418
↑ Katahira T, Nakagiri S, Terada K, Furukawa T. Secreted factor FAM3C (ILEI) is involved in retinal laminar formation. Biochem Biophys Res Commun. 2010 Feb 12;392(3):301-6. doi:, 10.1016/j.bbrc.2009.12.180. Epub 2010 Jan 6. PMID:20059962 doi:http://dx.doi.org/10.1016/j.bbrc.2009.12.180
↑ Jansson AM, Csiszar A, Maier J, Nystrom AC, Ax E, Johansson P, Holmberg Schiavone L. 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. 2017 Jul 27. pii: jbc.M117.782904. doi: 10.1074/jbc.M117.782904. PMID:28751379 doi:http://dx.doi.org/10.1074/jbc.M117.782904