Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom.
Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
Front Immunol. 2022 May 25;13:892234. doi: 10.3389/fimmu.2022.892234. eCollection 2022.
is an opportunistic pathogen that is able to thwart an effective host immune response by producing a range of immune evasion molecules, including binder of IgG (Sbi) which interacts directly with the central complement component C3, its fragments and associated regulators. Recently we reported the first structure of a disulfide-linked human C3d dimer and highlighted its potential role in modulating B-cell activation. Here we present an X-ray crystal structure of a disulfide-linked human C3d dimer, which undergoes a structurally stabilising N-terminal 3D domain swap when in complex with Sbi. These structural studies, in combination with circular dichroism and fluorescence spectroscopic analyses, reveal the mechanism underpinning this unique helix swap event and could explain the origins of a previously discovered N-terminally truncated C3dg dimer isolated from rat serum. Overall, our study unveils a novel staphylococcal complement evasion mechanism which enables the pathogen to harness the ability of dimeric C3d to modulate B-cell activation.
是一种机会性病原体，能够通过产生一系列免疫逃逸分子来挫败有效的宿主免疫反应，包括 IgG 结合蛋白（Sbi），它直接与中央补体成分 C3 及其片段和相关调节剂相互作用。最近，我们报告了第一个连接二硫键的人 C3d 二聚体的结构，并强调了其在调节 B 细胞激活中的潜在作用。在这里，我们展示了一个连接二硫键的人 C3d 二聚体的 X 射线晶体结构，当与 Sbi 结合时，它经历了结构稳定的 N 端 3D 结构域交换。这些结构研究与圆二色性和荧光光谱分析相结合，揭示了这种独特的螺旋交换事件的基础机制，并可以解释从大鼠血清中分离出的先前发现的 N 端截断 C3dg 二聚体的起源。总的来说，我们的研究揭示了一种新的葡萄球菌补体逃避机制，使病原体能够利用二聚体 C3d 来调节 B 细胞激活。
