Structural insights into the cis and trans assembly of human trophoblast cell surface antigen 2

Human trophoblast cell surface antigen 2 (TROP-2) is an important target of tumor therapy, and antibody-drug conjugates with sacituzumab targeting TROP-2 have been approved for the treatment of triple-negative breast cancer. Here, we report the crystal structures of TROP-2-ECD, which can be either cis-or trans-dimers depending on which distinct but overlapping interfaces is used to engage with monomers. The cis-or trans-tetrameric forms of TROP-2 can also be assembled with a non-overlapping interface with either cis- or trans-dimeriza-tion, suggesting that cis- and trans-dimers cluster on the cell surface. The binding site of sacituzumab on TROP-2 is mapped to be located on a stretched polypeptide in CPD (Q237-Q252), which is not involved in either cis-or trans -interactions. The present findings will improve understanding of the molecular assembly of TROP-2 on tumor cells and shed light on future design of biologics for tumor therapy.

Automated summary

The crystal structures of TROP-2-ECD show that TROP-2 can form either cis or trans dimers, and can assemble into tetramers through distinct interfaces. Sacituzumab binds to a stretched polypeptide in the CPD region of TROP-2, which is not involved in cis- or trans-interactions. These findings provide insights into the molecular assembly of TROP-2 on tumor cells and potential implications for the design of biologics for tumor therapy.