20.500.12556/RUL-136273 Trop2 forms a stable dimer with significant structural differences within the membrane-distal region as compared to EpCAM Trop2 is a cell-surface transmembrane glycoprotein involved in the maintenance of epithelial tissue integrity and is an important carcinoma marker. It shares similar claudin-interaction capacity with its paralogue EpCAM, and both are implicated in signaling triggered by proteolytic cleavage within the ectodomain. However, the cell proliferation-regulating interactions with IGF-1, neuregulin-1, and α$_5$β$_1$ integrin appear to be Trop2-specific. To illuminate the structural differences between Trop2 and EpCAM, we report the first crystal structure of a Trop2 ectodomain dimer and compare it to the analogous part of EpCAM. While the overall fold of the two proteins is similar, the dimers differ. In Trop2, the inter-subunit contacts are more extensive than in EpCAM, and there are two major differences in the membrane-distal regions. The immunogenic N-terminal domain is in Trop2 almost colinear with the dimer interface plain and consequently more laterally exposed, and the cleft of yet unknown functionality between the two subunits is almost absent. Furthermore, the site of initial signaling-associated proteolytic cleavage in Trop2 is accessible in the dimeric state, while in EpCAM dimer destabilization is required. The structural differences highlight the divergent evolutionary path of the two proteins and pave the way for their structure-based utilization in therapy. Trop2 extracellular part ectodomain Trop2EX crystal structure dimer EpCAM Trop2 zunajcelični del ektodomena Trop2EX kristalna struktura dimer EpCAM true false true Angleški jezik Slovenski jezik Članek v reviji 2022-04-21 15:20:23 2022-04-21 15:20:23 2022-09-15 04:13:40 0000-00-00 00:00:00 2021 0 0 15 str. iss. 19, art. 10640 Vol. 22 Oct. 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577.112 1422-0067 10.3390/ijms221910640 86938883 ijms-22-10640-v2.pdf ijms-22-10640-v2.pdf 1 3BABB6F2D47BEA0CFC7AEB65A21283F2 e452160e39233694924971f27610f25e40d977bb808e4ace3bb38ef7b978c554 042a2851-c176-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155828 https://www.mdpi.com/1422-0067/22/19/10640 0 bb78bc20-c175-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155827 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0