SpyA, a novel S. pyogenes ADP-ribosyltransferase

SpyA，一种新型化脓性链球菌 ADP-核糖基转移酶

• 批准号: 7145401
• 负责人: CARLEEN M. COLLINS
• 金额: $ 31.36万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145401
• 关键词: actins; clinical research; cytoskeletal proteins; family; infection; pentosyltransferase; phagocytosis; proteins; role; toxin; tropomyosin; vimentin

DESCRIPTION (provided by applicant): Streptococcus pyogenes is a ubiquitous and versatile human pathogen. Infections due to this organism range from the relatively mild and common pharyngitis and impetigo to the acute and life-threatening necrotizing fasciitis and toxic shock. The wide spectrum of streptococcal disease results in part from the production of the many and varied extracellular toxins and enzymes. The focus of this grant is a recently described streptococcal toxin we term Spy A, for S. pyogenes ADP-ribosylating toxin. SpyA transfers the ADP-ribose portion of NAD onto the cytoskeletal proteins vimentin, actin, and tropomyosin. While actin is modified by other ADP-ribosyltransferases, vimentin and tropomyosin are not common targets. Actin and vimentin filaments are needed for cellular functions requiring motility, such as cell migration during wound healing and phagocytosis. SpyA is a member of the C3 family of exotoxins, and similar to each member of this family, does not have an obvious receptor-binding domain, or associated binding domain as found with binary toxins. We proposed that SpyA gains entrance into the eukaryotic cell using a pore produced by the cholesterol dependent cytolysin SLO. The goals of this grant are (1) to determine the role of SpyA in streptococcal infections, (2) to characterize its novel entry mechanism and (3) to characterize the structure and biochemical activity of this toxin.

描述（由申请人提供）：化脓性链球菌是一种普遍存在且用途广泛的人类病原体。这种微生物引起的感染范围从相对轻微和常见的咽炎和脓疱病到急性和危及生命的坏死性筋膜炎和中毒性休克。广泛的链球菌疾病部分是由于多种不同的细胞外毒素和酶的产生造成的。这项资助的重点是最近描述的一种链球菌毒素，我们称之为 Spy A，即化脓性链球菌 ADP-核糖基化毒素。 SpyA 将 NAD 的 ADP-核糖部分转移到细胞骨架蛋白波形蛋白、肌动蛋白和原肌球蛋白上。虽然肌动蛋白被其他 ADP-核糖基转移酶修饰，但波形蛋白和原肌球蛋白并不是常见的靶标。肌动蛋白和波形蛋白丝是需要运动的细胞功能所必需的，例如伤口愈合和吞噬过程中的细胞迁移。 SpyA 是外毒素 C3 家族的成员，与该家族的每个成员相似，不具有明显的受体结合结构域，或二元毒素中发现的相关结合结构域。我们提出 SpyA 使用胆固醇依赖性溶细胞素 SLO 产生的孔进入真核细胞。这笔资助的目标是 (1) 确定 SpyA 在链球菌感染中的作用，(2) 表征其新颖的进入机制，以及 (3) 表征该毒素的结构和生化活性。