RELATION OF STREPTOCOCCAL M PROTEINS TO CARDIAC PROTEINS

链球菌 M 蛋白与心脏蛋白的关系

• 批准号: 3350528
• 负责人: BELUR N MANJULA
• 金额: $ 21.29万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3350528
• 关键词: Streptococcus infection; antibody; autoimmune disorder; enzyme linked immunosorbent assay; host organism interaction; human tissue; immunochemistry; medical complication; molecular pathology; monoclonal antibody; muscle proteins; myocardium; phagocytosis; radioimmunoassay; rheumatic fever; rheumatic heart disease; serology /serodiagnosis; virulence

Rheumatic fever and rheumatic heart damage are recognized to be sequelae of group A streptococcal infection. Antibodies cross-reactive with streptococcal components and mammalian muscle have been demonstrated in the sera of acute rheumatic fever patients. Our previous studies have shown that M protein, the type-specific antiphagocytic determinant of the group A streptococcus, has a coiled-coil structure similar to the mammalian muscle tropomyosin. More recently, we have established the complete amino acid sequence of a biologically active fragment of the M protein from the type 5 streptococcus, a 'rheumatogenic' serotype. This sequence is the first of its kind among the M proteins. A detailed analysis has now revealed that (i) the heptad periodicity in the nonpolar and charged amino acid residues, a characteristic of alpha-helical coiled-coil proteins, extends essentially throughout its entire length, and (ii) the distribution of charged functional groups in the external positions of its coiled-coil structure is different in the N- and the C-terminal regions of the molecule. In the proposed study, the potential significance of the similarity of the streptococcal M protein to mammalian coiled-coil proteins, and its relevance to the presence in the sera of acute rheumatic fever patients, of antibodies cross-reactive with streptococcal antigens and mammalian muscle will be investigated. Towards this objective, mammalian coiled-coil proteins tropomyosin and myosin will be isolated from human cardiac tissue, and their antigenic similarities with streptococcal M proteins will be examined by immunochemical methods. Also, sera from rheumatic fever patients will be examined for the presence of antibodies cross-reactive with M protein and muscle proteins. The contribution of charged functional groups for the stability of the coiled-coil structure, and for the integrity of the opsonogenic epitope of the M molecule will be explored by chemical modification studies. The structural relatedness of the M5 protein, as well as M proteins from other 'rheumatogenic' serotypes, to those of the 'nephritogenic' serotypes will be examined by comparative peptide map and immunochemical analysis. The results of these studies are expected to help us better understand (i) some aspects of the molecular basis for the pathogenesis of rheumatic fever, and thus possibly shed new light on the pathogenesis of autoimmune diseases in general and (ii) provide an insight into the structural characteristics governing the common antiphagocytic property of the M protein molecules.

风湿热和风湿性心脏损伤被认为是后遗症 A组链球菌感染。 抗体交叉反应 链球菌成分和哺乳动物肌肉已在 急性风湿热患者的血清。 我们以前的研究表明 该组A蛋白是A组A的类型特异性抗流细胞决定因素 链球菌具有类似于哺乳动物的卷曲线圈结构 tropomyosin。 最近，我们建立了完整的氨基酸 M蛋白的生物活性片段的序列来自5型 链球菌，一种“风湿性”血清型。 这个序列是第一个 它在M蛋白中。 详细的分析现在表明 （i）非极性和带电的氨基酸残基中的Heptad周期性， Alpha螺旋盘线圈蛋白的特征，基本上扩展 在整个长度上，（ii）电荷的分布 其盘绕线圈结构外部位置处于外部位置的功能组是 分子的N-和C末端区域不同。 在 拟议的研究，相似性的潜在意义 链球菌M蛋白到哺乳动物盘绕蛋白的蛋白质，其 与急性风湿热患者血清中的存在有关 抗体与链球菌抗原和哺乳动物肌肉交叉反应性 将被调查。 朝向这个目标，哺乳动物盘绕卷 蛋白质对肌动蛋白和肌球蛋白将从人类心脏组织中分离出来， 它们与链球菌M蛋白的抗原相似性将是 通过免疫化学方法检查。 另外，风湿热的血清 将检查患者是否存在抗体交叉反应的抗体 与M蛋白和肌肉蛋白。 充电功能的贡献 组稳定的盘绕结构的稳定性 M分子的开眼性表位的完整性将通过 化学修饰研究。 M5的结构相关性 蛋白质以及其他“风湿性”血清型的M蛋白质 “肾病”血清型将通过比较检查 肽图和免疫化学分析。 这些研究的结果是 希望帮助我们更好地理解（i）分子的某些方面 风湿热发病机理的基础，因此可能脱落新的 一般来说自身免疫性疾病的发病机理和（ii） 提供有关统治共同的结构特征的见解 M蛋白分子的抗癌细胞特性。