Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London SW7 2AZ, UK.
Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, UK.
Toxins (Basel). 2023 Jun 30;15(7):430. doi: 10.3390/toxins15070430.
CD59 is a GPI-anchored cell surface receptor that serves as a gatekeeper to controlling pore formation. It is the only membrane-bound inhibitor of the complement membrane attack complex (MAC), an immune pore that can damage human cells. While CD59 blocks MAC pores, the receptor is co-opted by bacterial pore-forming proteins to target human cells. Recent structures of CD59 in complexes with binding partners showed dramatic differences in the orientation of its ectodomain relative to the membrane. Here, we show how GPI-anchored CD59 can satisfy this diversity in binding modes. We present a PyLipID analysis of coarse-grain molecular dynamics simulations of a CD59-inhibited MAC to reveal residues of complement proteins (C6:Y285, C6:R407 C6:K412, C7:F224, C8β:F202, C8β:K326) that likely interact with lipids. Using modules of the MDAnalysis package to investigate atomistic simulations of GPI-anchored CD59, we discover properties of CD59 that encode the flexibility necessary to bind both complement proteins and bacterial virulence factors.
CD59 是一种糖基磷脂酰肌醇（GPI）锚定的细胞表面受体，作为控制孔形成的守门员。它是补体膜攻击复合物（MAC）的唯一膜结合抑制剂，MAC 是一种可以破坏人类细胞的免疫孔。虽然 CD59 阻止 MAC 孔的形成，但该受体被细菌形成孔的蛋白质劫持，以靶向人类细胞。最近 CD59 与结合伙伴的复合物的结构显示，其外域相对于膜的取向存在显著差异。在这里，我们展示了 GPI 锚定的 CD59 如何满足这种结合模式的多样性。我们展示了 PyLipID 对 CD59 抑制的 MAC 的粗粒度分子动力学模拟的分析，以揭示补体蛋白（C6:Y285、C6:R407 C6:K412、C7:F224、C8β:F202、C8β:K326）的残基可能与脂质相互作用。使用 MDAnalysis 包的模块研究 GPI 锚定的 CD59 的原子模拟，我们发现了 CD59 的特性，这些特性编码了与补体蛋白和细菌毒力因子结合所必需的灵活性。
