Allosteric Regulation of Fibronectin/α5β1 Interaction by Fibronectin-Binding MSCRAMMs.
Allosteric Regulation of Fibronectin/α5β1 Interaction by Fibronectin-Binding MSCRAMMs.
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DOI：
10.1371/journal.pone.0159118
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Höök M
中科院分区：
文献类型：
--
作者：
Liang X;Garcia BL;Visai L;Prabhakaran S;Meenan NA;Potts JR;Humphries MJ;Höök M
微生物对宿主组织的粘附是感染性疾病的标志，并且通常由一类称为MSCRAlectin（识别粘附基质分子的微生物表面组分）的粘附素介导。许多病原体表达特异性结合异源二聚体人糖蛋白纤连蛋白（Fn）的MSCRA。除了在粘附中的作用之外，Fn结合MSCRA还利用生理Fn功能。例如，几种病原体可以通过MSCRAMM结合的Fn桥接与α 5 β 1整联蛋白相互作用的机制侵入宿主细胞。本研究通过对两种Fn结合MSCRAMM--FnBPA（金黄色葡萄球菌）和BBK32（伯氏疏螺旋体）的研究，探讨MSCRAMM诱导Fn/α 5 β 1整合素活化的构效关系。圆二色谱，荧光共振能量转移，和动态光散射技术揭示了一个构象重排的Fn涉及域远离MSCRAMM结合位点。表面等离子体共振实验证明在FnBPA或BBK32存在下Fn/α 5 β 1整联蛋白亲和力显著增强。对这些相互作用的详细动力学分析表明，亲和力的这种变化可仅归因于初始Fn/α 5 β 1结合速率的增加，并且这种速率增强依赖于MSCRAlidine的高亲和力Fn结合。这些数据表明，MSCRAMM诱导的Fn异源二聚体内特异性分子内接触的扰动通过暴露先前隐藏的α 5 β 1相互作用基序而导致活化。通过将Fn中的结构变化与Fn/α 5 β 1亲和力增加的直接测量相关联，这项工作显著地推进了我们对Fn结合MSCRA调节整合素功能的结构基础的理解。
Adherence of microbes to host tissues is a hallmark of infectious disease and is often mediated by a class of adhesins termed MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules). Numerous pathogens express MSCRAMMs that specifically bind the heterodimeric human glycoprotein fibronectin (Fn). In addition to roles in adhesion, Fn-binding MSCRAMMs exploit physiological Fn functions. For example, several pathogens can invade host cells by a mechanism whereby MSCRAMM-bound Fn bridges interaction with α5β1 integrin. Here, we investigate two Fn-binding MSCRAMMs, FnBPA (Staphylococcus aureus) and BBK32 (Borrelia burgdorferi) to probe structure-activity relationships of MSCRAMM-induced Fn/α5β1integrin activation. Circular dichroism, fluorescence resonance energy transfer, and dynamic light scattering techniques uncover a conformational rearrangement of Fn involving domains distant from the MSCRAMM binding site. Surface plasmon resonance experiments demonstrate a significant enhancement of Fn/α5β1 integrin affinity in the presence of FnBPA or BBK32. Detailed kinetic analysis of these interactions reveal that this change in affinity can be attributed solely to an increase in the initial Fn/α5β1 on-rate and that this rate-enhancement is dependent on high-affinity Fn-binding by MSCRAMMs. These data implicate MSCRAMM-induced perturbation of specific intramolecular contacts within the Fn heterodimer resulting in activation by exposing previously cryptic α5β1 interaction motifs. By correlating structural changes in Fn to a direct measurement of increased Fn/α5β1 affinity, this work significantly advances our understanding of the structural basis for the modulation of integrin function by Fn-binding MSCRAMMs.