Structure and Function of a Fungal Adhesin that Binds Heparin and Mimics Thrombospondin-1 by Blocking T Cell Activation and Effector Function

T. Tristan Brandhorst, René Roy, Marcel Wüthrich, Som Nanjappa, Hanna Filutowicz, Kevin Galles, Marco Tonelli, Darrell R. McCaslin, Kenneth Satyshur, Bruce Klein

Research output: Contribution to journalArticle

Abstract

Blastomyces adhesin-1 (BAD-1) is a 120-kD surface protein on B. dermatitidis yeast. We show here that BAD-1 contains 41 tandem repeats and that deleting even half of them impairs fungal pathogenicity. According to NMR, the repeats form tightly folded 17-amino acid loops constrained by a disulfide bond linking conserved cysteines. Each loop contains a highly conserved WxxWxxW motif found in thrombospondin-1 (TSP-1) type 1 heparin-binding repeats. BAD-1 binds heparin specifically and saturably, and is competitively inhibited by soluble heparin, but not related glycosaminoglycans. According to SPR analysis, the affinity of BAD-1 for heparin is 33 nM±14 nM. Putative heparin-binding motifs are found both at the N-terminus and within each tandem repeat loop. Like TSP-1, BAD-1 blocks activation of T cells in a manner requiring the heparan sulfate-modified surface molecule CD47, and impairs effector functions. The tandem repeats of BAD-1 thus confer pathogenicity, harbor motifs that bind heparin, and suppress T-cell activation via a CD47-dependent mechanism, mimicking mammalian TSP-1.

Original languageEnglish (US)
Article numbere1003464
JournalPLoS pathogens
Volume9
Issue number7
DOIs
StatePublished - Jul 2013

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Brandhorst, T. T., Roy, R., Wüthrich, M., Nanjappa, S., Filutowicz, H., Galles, K., Tonelli, M., McCaslin, D. R., Satyshur, K., & Klein, B. (2013). Structure and Function of a Fungal Adhesin that Binds Heparin and Mimics Thrombospondin-1 by Blocking T Cell Activation and Effector Function. PLoS pathogens, 9(7), [e1003464]. https://doi.org/10.1371/journal.ppat.1003464