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

Meng Sun1,2, Helin Zhang1,2, Min Jiang2,3,4

  • 1Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.

Iscience
|October 25, 2021
PubMed

Insights

Human trophoblast cell surface antigen 2 (TROP-2) forms dimers and tetramers on tumor cells. Sacituzumab’s binding site on TROP-2 is separate from these interactions, informing future cancer therapy designs.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Oncology

Background:

  • Human trophoblast cell surface antigen 2 (TROP-2) is a key target in cancer therapy.
  • Sacituzumab, an antibody-drug conjugate targeting TROP-2, is approved for triple-negative breast cancer treatment.

Purpose of the Study:

  • To determine the crystal structures of TROP-2 extracellular domain (ECD).
  • To elucidate the molecular assembly and dimerization/tetramerization interfaces of TROP-2.
  • To map the binding site of sacituzumab on TROP-2.

Main Methods:

  • X-ray crystallography to determine TROP-2-ECD structures.
  • Analysis of distinct interfaces involved in TROP-2 monomer interactions.
  • Mapping of the sacituzumab binding epitope on TROP-2.

Main Results:

  • TROP-2-ECD forms cis- or trans-dimers via distinct interfaces.
  • TROP-2 can assemble into cis- or trans-tetramers through non-overlapping interfaces.
  • Sacituzumab binds to a TROP-2 polypeptide region (Q237-Q252) not involved in dimerization/tetramerization.

Conclusions:

  • TROP-2 dimers and tetramers likely cluster on tumor cell surfaces.
  • Understanding TROP-2 assembly provides insights into its role in tumor biology.
  • Findings will guide the rational design of novel TROP-2-targeting biologics for cancer therapy.
Keywords:
CancerImmunologyStructural biology

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