Fibrinogen Activates the Capture of Human Plasminogen by Staphylococcal Fibronectin-Binding Proteins.
Fibrinogen Activates the Capture of Human Plasminogen by Staphylococcal Fibronectin-Binding Proteins.
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DOI：
10.1128/mbio.01067-17
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发表时间：
2017-09-05
期刊：
影响因子：
6.4
通讯作者：
Dufrêne YF
中科院分区：
文献类型：
--
作者：
Herman-Bausier P;Pietrocola G;Foster TJ;Speziale P;Dufrêne YF
侵袭性细菌病原体可以捕获宿主的纤溶酶原（Plg）并使其形成纤溶酶。这一过程具有重要的医学意义，因为表面结合的纤溶蛋白通过切割组织成分促进细菌传播，并通过降解调理素促进免疫逃避。在金黄色葡萄球菌中，Plg的结合部分由细胞表面纤维连接蛋白结合蛋白（FnBPs）介导，但其潜在的分子机制尚不清楚。在这里，我们使用单细胞和单分子技术来证明FnBPs通过涉及纤维蛋白原（Fg）的复杂激活机制捕获Plg，纤维蛋白原是血液中发现的另一种配体。我们发现，虽然FnBPs通过弱（~ 200-pN）分子键与Plg结合，但通过高亲和的dock、lock和latch机制与Fg的直接相互作用显著增加了FnBPs -Plg键的强度（高达~ 2000 -pN）。我们的研究结果指出了一种新的模型，其中Fg的结合引发了FnBP蛋白的主要构象变化，导致埋藏的Plg结合结构域被投射并暴露在远离细胞表面的地方，从而促进了与Plg的强相互作用。这项研究证明了葡萄球菌细胞表面蛋白在配体结合相互作用中的一个先前未被发现的作用，即改变蛋白质取向来激活一种隐藏的生物学功能。金黄色葡萄球菌通过细胞壁纤维连接蛋白结合蛋白（FnBPs）捕获人纤溶酶原（Plg），但其潜在的分子机制尚不清楚。本研究表明，金黄色葡萄球菌表面Plg和FnBPs相互作用的力很弱。然而，我们发现纤维蛋白原与FnBPs的结合显著增强了FnBPs -Plg的结合，从而揭示了Fg在金黄色葡萄球菌捕获Plg中的意想不到的作用。这些实验支持一种模型，即fg诱导的FnBPs构象变化促进了它们与Plg的相互作用。这项工作揭示了以前未描述的葡萄球菌表面蛋白的激活机制，即配体结合引发了一种神秘的生物学功能。
Invasive bacterial pathogens can capture host plasminogen (Plg) and allow it to form plasmin. This process is of medical importance as surface-bound plasmin promotes bacterial spread by cleaving tissue components and favors immune evasion by degrading opsonins. In Staphylococcus aureus, Plg binding is in part mediated by cell surface fibronectin-binding proteins (FnBPs), but the underlying molecular mechanism is not known. Here, we use single-cell and single-molecule techniques to demonstrate that FnBPs capture Plg by a sophisticated activation mechanism involving fibrinogen (Fg), another ligand found in the blood. We show that while FnBPs bind to Plg through weak (∼200-pN) molecular bonds, direct interaction of the adhesins with Fg through the high-affinity dock, lock, and latch mechanism dramatically increases the strength of the FnBP-Plg bond (up to ∼2,000 pN). Our results point to a new model in which the binding of Fg triggers major conformational changes in the FnBP protein, resulting in the buried Plg-binding domains being projected and exposed away from the cell surface, thereby promoting strong interactions with Plg. This study demonstrated a previously unidentified role for a ligand-binding interaction by a staphylococcal cell surface protein, i.e., changing the protein orientation to activate a cryptic biological function. Staphylococcus aureus captures human plasminogen (Plg) via cell wall fibronectin-binding proteins (FnBPs), but the underlying molecular mechanism is not known. Here we show that the forces involved in the interaction between Plg and FnBPs on the S. aureus surface are weak. However, we discovered that binding of fibrinogen to FnBPs dramatically strengthens the FnBP-Plg bond, therefore revealing an unanticipated role for Fg in the capture of Plg by S. aureus. These experiments favor a model where Fg-induced conformational changes in FnBPs promote their interaction with Plg. This work uncovers a previously undescribed activation mechanism for a staphylococcal surface protein, whereby ligand-binding elicits a cryptic biological function.