Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna Pot 113, SI-1000 Ljubljana, Slovenia.
Int J Mol Sci. 2021 Sep 30;22(19):10640. doi: 10.3390/ijms221910640.
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 αβ 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 是一种细胞表面跨膜糖蛋白，参与维持上皮组织完整性，是一种重要的癌标志物。它与它的同源物 EpCAM 具有相似的 Claudin 相互作用能力，并且两者都与蛋白水解切割在细胞外结构域内引发的信号有关。然而，与 IGF-1、神经调节素-1 和 αβ 整合素的细胞增殖调节相互作用似乎是 Trop2 特有的。为了阐明 Trop2 和 EpCAM 之间的结构差异，我们报告了 Trop2 细胞外结构域二聚体的第一个晶体结构，并将其与 EpCAM 的类似部分进行了比较。虽然两种蛋白质的整体折叠相似，但二聚体却不同。在 Trop2 中，亚基间的接触比 EpCAM 更广泛，并且在膜远侧区域有两个主要差异。免疫原性的 N 端结构域在 Trop2 中几乎与二聚体界面平面共线，因此更侧向暴露，而两个亚基之间尚未确定功能的裂隙几乎不存在。此外，Trop2 中初始信号相关蛋白水解切割位点在二聚体状态下是可及的，而在 EpCAM 中二聚体的不稳定性是必需的。结构差异突出了两种蛋白质的不同进化途径，并为它们基于结构的治疗利用铺平了道路。
