Multifunctional Roles of AgI/II Family Proteins

项目摘要 链球菌通过其表面蛋白促进重要器官的感染，从而促进其 黏附、定植和生物膜的形成。在口腔中，变形链球菌使用其表面粘附素agi/ii和 Gbpc用于初始黏附Gp340，葡聚糖用于促进生物膜的形成，在某些情况下 被合并到生物膜中的其他微生物。更广泛地说，链球菌种的许多成员 表达一种类似AgI/II的同源基因，它们用来附着共同的和物种特定的靶点，暗示 它们导致了涉及这些链球菌的感染的疾病状态。在物理损坏的地方 对于牙床或牙周病，链球菌可以渗透到血流中，成为全身性的机会主义者。 病原体。 这项建议侧重于表征宿主-微生物和微生物-微生物的分子机制 涉及AgI/II-蛋白质家族的相互作用。在Sspb的结构研究中，Deivanayagam实验室发现 V区内的一个与多肽结合的裂隙，一个共同的裂隙，包含一个钙离子。该多肽具有纳米分子。 与SspB、AgI/II和gbpc的V区黏附；该肽抑制V区与SRCR的黏附 Gp340区域，并减少生物膜的形成。在对gbpc的研究中，这种裂隙被证明也参与了 V区对葡聚糖的粘附性。我们的初步研究表明，不仅有共同的遵守目标，而且 还保留了坚持的领域。 AgI/II家族蛋白的顶端V区和细胞壁锚定的C末端区域都被证明是 参与粘合主机表面。在这个提案中，我们计划调查这样一个假设： AgI/II家族蛋白之间的细胞外基质(ECM)蛋白相互作用具有相似但不同的基序 导致口腔外感染的开始或进展。具体目标是：1. 研究AgI/II家族蛋白与细胞外基质之间的相互作用。目的2：确定AgI/II蛋白的能力 与其他病原微生物相互作用。拟议的研究将阐明共同遵守的领域。 为了确定设计抑制剂以防止相互作用的可能性，这种相互作用将降低 这些链球菌会导致感染和疾病。

Project Summary Streptococcal bacteria contribute to infections of vital organs through their surface proteins which facilitate their adherence, colonization, and biofilm formation. In the oral cavity, S. mutans use its surface adhesins AgI/II and GbpC to adhere to Gp340 for initial adherence, dextran to promote biofilm development, and in some cases other microbes which are incorporated into biofilms. More generally many members of the streptococcal species express an AgI/II-like homolog which they use to adhere to both shared and species-specific targets, implicating them in contributing to the disease state of infections involving these streptococci. At sites of physical damage to gums or gum disease, streptococcal species can infiltrate the blood stream and become systemic opportunistic pathogens. This proposal focuses on characterizing the molecular mechanisms of host-microbe and microbe-microbe interactions involving the AgI/II-family of proteins. In structural studies of SspB the Deivanayagam lab discovered a peptide-binding cleft within the V-region, a shared cleft housing a calcium ion. This peptide has nanomolar adherence with the V-regions of SspB, AgI/II and GbpC; the peptide inhibits the V-regions adherence to SRCR region of Gp340 and reduces biofilm formation. In studies with GbpC, this cleft was shown to also be involved in the V-regions adherence to dextran. Our preliminary studies have shown not only shared adherence targets, but also conserved areas of adherence. Both the apical V-region and cell-wall anchored C-terminal regions of AgI/II-family proteins have been shown to be involved in adherence host surfaces. In this proposal we plan to investigate the hypothesis that the Extracellular matrix (ECM) protein interactions among AgI/II-family proteins would share similar but distinct motifs that contribute to the initiation or progression of infections outside the oral cavity. The specific aims are Aim1: Characterize the interactions between AgI/II-family proteins and ECMs. Aim 2: Determine AgI/II proteins’ ability to interact with other pathogenic microorganisms. The proposed studies will elucidate shared areas of adherence to determine the potential for designing inhibitors to prevent the interaction which would reduce the ability of these streptococci to contribute to infection and disease.