Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
mBio. 2021 Aug 31;12(4):e0116721. doi: 10.1128/mBio.01167-21. Epub 2021 Aug 3.
Staphylococcus aureus can target a variety of tissues, causing life-threatening infections. The basis for this diversity stems from the microorganism's ability to spread in the vascular system throughout the body. To survive in blood, S. aureus coats itself with a fibrinogen (Fg)/fibrin shield. The protective shield is assembled by the coordinated actions of a number of Fg-binding bacterial proteins that manipulate the host's blood coagulation system. Several of the Fg binders appear redundant, sharing similar functional motifs. This observation led us to screen for the presence of novel proteins with significant amino acid identities to von Willebrand factor-binding protein (vWbp), a key component in the shield assembly machinery. One identified protein showed significant sequence identity with the C-terminal region of vWbp, and we consequently named it vWbp homologous protein (vhp). The gene lies within a cluster of genes that encode other virulence factors in S. aureus. Although each isolate only contains one copy of the gene, S. aureus has at least three distinct alleles, , , and , that are present in the core genome. All three vhp isoforms bind Fg with high affinity, targeting a site located in the D fragment of Fg. We further identified an ∼79 amino acid-long, conserved segment within the C-terminal region of vWbp that shares high sequence identities (54 to 67%) with the vhps and binds soluble Fg with high affinity. Further analysis of this conserved motif and the intact vhps revealed intriguing differences in the Fg binding behavior, perhaps suggesting that these proteins have similar but discrete functions in the shield assembly. The life-threatening diseases caused by multidrug-resistant Staphylococcus aureus strains are a worldwide medical problem due to treatment limitations and the lack of an effective vaccine. The ability of S. aureus to coat itself with a protective fibrinogen (Fg)/fibrin shield allows the organism to survive in blood and to disseminate and cause invasive diseases. This process represents a promising target for novel antistaphylococcal treatment strategies but is incompletely understood. S. aureus expresses a number of Fg-binding proteins. Some of these proteins have apparently redundant functions. Proteins with similar functions often share a structural or functional motif with each other. In this study, we identified a protein homologous to the C-terminal of von Willebrand factor-binding protein (vWbp), a key contributor in the Fg shield assembly that also binds Fg. Further analysis allowed us to identify a common Fg-binding motif.
金黄色葡萄球菌可以攻击多种组织，引发危及生命的感染。这种多样性的基础源于该微生物在全身血管系统中传播的能力。为了在血液中存活，金黄色葡萄球菌用纤维蛋白原 (Fg)/纤维蛋白盾牌包裹自身。该保护盾由许多纤维蛋白结合细菌蛋白的协调作用组装而成，这些蛋白操纵宿主的血液凝固系统。一些纤维蛋白结合物似乎是多余的，它们具有相似的功能基序。这一观察结果促使我们筛选出与 von Willebrand 因子结合蛋白 (vWbp) 具有显著氨基酸同一性的新型蛋白质，vWbp 是盾牌组装机械中的关键组成部分。一种鉴定出的蛋白质与 vWbp 的 C 端区域具有显著的序列同一性，因此我们将其命名为 vWbp 同源蛋白 (vhp)。 基因位于编码金黄色葡萄球菌其他毒力因子的基因簇内。尽管每个分离株仅含有一个 基因拷贝，但金黄色葡萄球菌至少有三个不同的等位基因 、 、和 ，它们存在于核心基因组中。所有三种 vhp 同工型都与 Fg 具有高亲和力结合，靶向 Fg 的 D 片段中的一个位点。我们进一步鉴定出 vWbp 的 C 端区域内一个约 79 个氨基酸长的保守片段，与 vhps 具有高度的序列同一性（54 至 67%），并与可溶性 Fg 具有高亲和力结合。对该保守基序和完整 vhps 的进一步分析揭示了 Fg 结合行为的有趣差异，这表明这些蛋白质在盾牌组装中具有相似但不同的功能。 由于治疗局限性和缺乏有效的疫苗，耐多药金黄色葡萄球菌菌株引起的危及生命的疾病是一个全球性的医学问题。金黄色葡萄球菌用保护性纤维蛋白原 (Fg)/纤维蛋白盾牌包裹自身的能力使该生物体能够在血液中存活并传播并引起侵袭性疾病。该过程代表了一种有前途的新型抗葡萄球菌治疗策略的靶点，但尚未完全理解。金黄色葡萄球菌表达许多纤维蛋白结合蛋白。其中一些蛋白具有明显的冗余功能。具有相似功能的蛋白通常彼此共享结构或功能基序。在这项研究中，我们鉴定出一种与 von Willebrand 因子结合蛋白 (vWbp) 的 C 端同源的蛋白，vWbp 是 Fg 盾牌组装的关键贡献者，也与 Fg 结合。进一步的分析使我们能够识别出一个常见的 Fg 结合基序。
