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

PLoS Pathogens

T. Tristan Brandhorst¹  René Roy¹  Hanna Filutowicz¹  Darrell R. McCaslin¹  Marco Tonelli¹  Kevin Galles¹  Som Nanjappa²  Kenneth Satyshur³  Bruce Klein³  Marcel Wüthrich⁴ 

[1] Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America;The Cell and Molecular Biology Graduate Training Program, College of Agriculture and Life Science, University of Wisconsin-Madison, Madison, Wisconsin, United States of America;The Department of Biochemistry, The Biophysics Instrumentation Facility, College of Agriculture and Life Science, University of Wisconsin-Madison, Madison, Wisconsin, United States of America;The Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America

关键词: Heparin;    T;    em repeats;    T cells;    Blastomyces dermatitidis;    Tryptophan;    Fungal pathogens;    Sequence motif analysis;    Yeast infections;   

DOI  :  10.1371/journal.ppat.1003464

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY