Trop2 forms a stable dimer with significant structural differences within the membrane-distal region as compared to EpCAM

Pavšič, Miha (author)

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.

• Language: English
• Keywords: Trop2, extracellular part, ectodomain, Trop2EX, crystal structure, dimer, EpCAM
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 15 str.
• Numbering: Vol. 22, iss. 19, art. 10640
• PID: 20.500.12556/RUL-136273
• UDC: 577.112
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms221910640
• COBISS.SI-ID: 86938883
• Publication date in RUL: 21.04.2022

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 01.10.2021

Secondary language

• Language: Slovenian
• Keywords: Trop2, zunajcelični del, ektodomena, Trop2EX, kristalna struktura, dimer, EpCAM

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0207
• Name: Toksini in biomembrane

• Funder: ARRS - Slovenian Research Agency
• Project number: J1-7119
• Name: Biologija EpCAM na strukturnem nivoju kot osnova za učinkovito tumorsko ciljanje