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Scientific article
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The choanoflagellate pore-forming lectin SaroL-1 punches holes in cancer cells by targeting the tumor-related glycosphingolipid Gb3

Published inCommunications biology, vol. 5, no. 1, 954
Publication date2022-09-12
First online date2022-09-12
Abstract

Abstract

Choanoflagellates are primitive protozoa used as models for animal evolution. They express a large variety of multi-domain proteins contributing to adhesion and cell communication, thereby providing a rich repertoire of molecules for biotechnology. Adhesion often involves proteins adopting a β-trefoil fold with carbohydrate-binding properties therefore classified as lectins. Sequence database screening with a dedicated method resulted in TrefLec, a database of 44714 β-trefoil candidate lectins across 4497 species. TrefLec was searched for original domain combinations, which led to single out SaroL-1 in the choanoflagellate Salpingoeca rosetta , that contains both β-trefoil and aerolysin-like pore-forming domains. Recombinant SaroL-1 is shown to bind galactose and derivatives, with a stronger affinity for cancer-related α-galactosylated epitopes such as the glycosphingolipid Gb3, when embedded in giant unilamellar vesicles or cell membranes. Crystal structures of complexes with Gb3 trisaccharide and GalNAc provided the basis for building a model of the oligomeric pore. Finally, recognition of the αGal epitope on glycolipids required for hemolysis of rabbit erythrocytes suggests that toxicity on cancer cells is achieved through carbohydrate-dependent pore-formation.

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Funding
  • Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg - [Az: 33-7532.20]
  • Deutsche Forschungsgemeinschaft - [EXC-2189]
  • Agence Nationale de la Recherche - [ANR-15-IDEX-02]
  • European Commission - Synthetic biology of carbohydrate-binding proteins: engineering protein-carbohydrate interactions for diagnostics and cell targeting [814029]
Citation (ISO format)
NOTOVA, Simona et al. The choanoflagellate pore-forming lectin SaroL-1 punches holes in cancer cells by targeting the tumor-related glycosphingolipid Gb3. In: Communications biology, 2022, vol. 5, n° 1, p. 954. doi: 10.1038/s42003-022-03869-w
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ISSN of the journal2399-3642
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