Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
PLoS Pathog. 2013;9(7):e1003464. doi: 10.1371/journal.ppat.1003464. Epub 2013 Jul 11.
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.
芽生菌黏附素-1（BAD-1）是一种存在于皮炎芽生菌酵母表面的 120kD 蛋白。我们的研究显示 BAD-1 包含 41 个串联重复序列，即使删除一半也会损害真菌的致病性。根据 NMR 研究，这些重复序列形成紧密折叠的 17 个氨基酸环，由连接保守半胱氨酸的二硫键固定。每个环都包含一个高度保守的 WxxWxxW 基序，该基序存在于血小板反应素-1（TSP-1）Ⅰ型肝素结合重复序列中。BAD-1 特异性和饱和结合肝素，并可被可溶性肝素竞争性抑制，但不与相关糖胺聚糖结合。根据 SPR 分析，BAD-1 与肝素的亲和力为 33 nM±14 nM。在 N 端和每个串联重复环内都发现了假定的肝素结合基序。与 TSP-1 相似，BAD-1 通过需要硫酸乙酰肝素修饰表面分子 CD47 的方式抑制 T 细胞的激活，并损害效应功能。因此，BAD-1 的串联重复序列赋予了致病性，具有结合肝素的基序，并通过 CD47 依赖性机制抑制 T 细胞激活，模拟了哺乳动物的 TSP-1。
