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


ABSTRACT: 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-dimerization, 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.

SUBMITTER: Sun M 

PROVIDER: S-EPMC8517388 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Structural insights into the <i>cis</i> and <i>trans</i> assembly of human trophoblast cell surface antigen 2.

Sun Meng M   Zhang Helin H   Jiang Min M   Chai Yan Y   Qi Jianxun J   Gao George F GF   Tan Shuguang S  

iScience 20210930 10


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 <i>cis-</i> or <i>trans-</i>dimers depending on which distinct but overlapping interfaces is used to engage with monomers. The <i>cis-</i> or <i>trans</i>-tetrameric forms of TROP-2 can also be assembl  ...[more]

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