title: Structure and function of a fungal adhesin that binds heparin and mimics thrombospondin-1 by blocking T cell activation and effector function.
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.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: T Tristan
authors.initials: TT
authors.lastname: Brandhorst
authors.forename: René
authors.initials: R
authors.lastname: Roy
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
authors.forename: Som
authors.initials: S
authors.lastname: Nanjappa
authors.forename: Hanna
authors.initials: H
authors.lastname: Filutowicz
authors.forename: Kevin
authors.initials: K
authors.lastname: Galles
authors.forename: Marco
authors.initials: M
authors.lastname: Tonelli
authors.forename: Darrell R
authors.initials: DR
authors.lastname: McCaslin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Satyshur
authors.forename: Bruce
authors.initials: B
authors.lastname: Klein
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001758:Blastomyces / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D001759:Blastomycosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051928:CD47 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008297:Male; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020080:Tandem Repeat Sequences; D019700:Thrombospondin 1 / Q000737:chemistry / Q000378:metabolism; D014774:Virulence
chemical_list: D000946:Antigens, Fungal; D000954:Antigens, Surface; D051928:CD47 Antigen; D005656:Fungal Proteins; D050505:Mutant Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D006493:Heparin