7pee | pdb_00007pee
Crystal structure of extracellular part of human Trop2
Structural highlights
Disease[TACD2_HUMAN] Honey-droplet corneal dystrophy;Gelatinous drop-like corneal dystrophy. The disease is caused by mutations affecting the gene represented in this entry. Function[TACD2_HUMAN] May function as a growth factor receptor. Publication Abstract from PubMedTrop2 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 alpha5beta1 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 Forms a Stable Dimer with Significant Structural Differences within the Membrane-Distal Region as Compared to EpCAM.,Pavsic M Int J Mol Sci. 2021 Sep 30;22(19). pii: ijms221910640. doi:, 10.3390/ijms221910640. PMID:34638982[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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