"Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes".
"Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes".
复制标题
“莱姆病和回归热螺旋体 C1r 抑制剂蛋白的构象动力学”。
DOI：
10.1101/2023.03.01.530473
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Garcia,BrandonL
中科院分区：
文献类型：
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作者：
Roy,Sourav;BoothJr,CharlesE;Powell-Pierce,AlexandraD;Schulz,AnnaM;Skare,JonT;Garcia,BrandonL
疏螺旋体病原体是莱姆病、回归热和宫本疏螺旋体病的媒介传播病原体。这些螺旋体各自编码几种表面定位的脂蛋白，其结合到人类补体系统的组分。BBK 32是疏螺旋体脂蛋白的一个实例，其保护莱姆病螺旋体免受补体介导的攻击。BBK 32的补体抑制活性源自α螺旋C末端结构域，其直接与经典途径的起始蛋白酶C1 r相互作用。Borrelia miyamotoi螺旋体编码BBK 32直系同源物，称为FbpA和FbpB，这些蛋白质也抑制C1 r，尽管通过不同的识别机制。C1 r抑制活性的第三个直系同源物称为FbpC，这是专门在回归热螺旋体中发现的，仍然未知。在这里，我们报告的C-末端结构域的B的晶体结构。hermsii FbpC至1.5 μ m的极限分辨率。表面等离子体共振研究和补体功能测定表明，FbpC保留了有效的BBK 32样抗补体活性。基于FbpC的结构，我们假设疏螺旋体C1 r抑制剂的补体抑制结构域的构象动力学可能不同。为了验证这一点，我们利用BBK 32、FbpA、FbpB和FbpC的C端结构域的晶体结构进行了1 µs的分子动力学模拟，结果显示疏螺旋体C1 r抑制剂采用了由两个功能关键区域定义的能量有利的开放和闭合状态。这项研究推进了我们对蛋白质动力学如何有助于细菌免疫逃避蛋白功能的理解，并揭示了疏螺旋体C1 r抑制剂结构的惊人可塑性。
Borrelial pathogens are vector-borne etiological agents of Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind to components of the human complement system. BBK32 is an example of a borrelial lipoprotein that protects the Lyme disease spirochete from complement-mediated attack. The complement inhibitory activity of BBK32 arises from an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical pathway, C1r. Borrelia miyamotoi spirochetes encode BBK32 orthologs termed FbpA and FbpB, and these proteins also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever spirochetes, remains unknown. Here we report the crystal structure of the C-terminal domain of B. hermsii FbpC to a limiting resolution of 1.5 Å. Surface plasmon resonance studies and assays of complement function demonstrate that FbpC retains potent BBK32-like anti-complement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out 1 µs molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. This study advances our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveals a surprising plasticity in the structures of borrelial C1r inhibitors.