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

  • iScience. 2021 Sep 30;24(10):103190. doi: 10.1016/j.isci.2021.103190.
Meng Sun  1  2 ,  Helin Zhang  1  2 ,  Min Jiang  2  3  4 ,  Yan Chai  3 ,  Jianxun Qi  2  3 ,  George F Gao  1  2  3  4 ,  Shuguang Tan  2  3
Affiliations
  • 1. Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 4. Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 34693228 DOI: 10.1016/j.isci.2021.103190
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.

Keywords
Cancer; Immunology; Structural biology.
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