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

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. © 2013 brandhorst et al.