Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Marine Biological Laboratory, Woods Hole, MA, United States.
Front Immunol. 2024 Sep 16;15:1466865. doi: 10.3389/fimmu.2024.1466865. eCollection 2024.
C-reactive protein (CRP) binds to phosphocholine (PCh)-containing substances and subsequently activates the complement system to eliminate the ligand. The PCh-binding function of CRP has been conserved throughout evolution from arthropods to humans. Human CRP, in its structurally altered conformation at acidic pH, also binds to amyloid-β (Aβ) and prevents the formation of Aβ fibrils. It is unknown whether the Aβ-binding function of CRP has also been evolutionarily conserved. The aim of this study was to determine whether CRP isolated from American horseshoe crab was also anti-amyloidogenic and whether this function required structural alteration of CRP (Li-CRP). Two CRP species Li-CRP-I and Li-CRP-II were purified from hemolymph by employing PCh-affinity chromatography and phosphoethanolamine-affinity chromatography, respectively. Both Li-CRP-I and Li-CRP-II bound to immobilized Aβ at physiological pH. Unlike human CRP, Li-CRP did not require any changes in its overall structure to bind to Aβ. Both Li-CRP-I and Li-CRP-II bound to Aβ in the fluid phase also and prevented the fibrillation of Aβ. Additionally, ion-exchange chromatography of purified Li-CRP indicated that a variety of Li-CRP molecules of different subunit compositions were present in hemolymph, raising the possibility that the presence of various Li-CRP species in hemolymph facilitates the recognition of a range of proteins with differing amyloidogenicity. We conclude that the binding of CRP to Aβ is an ancient function of CRP. In invertebrates, the Aβ-binding function of CRP can protect the host from toxicity caused by amyloidogenic and pathogenic proteins. In humans, the Aβ-binding function of CRP can protect against inflammatory diseases in which the host proteins are ectopically deposited on either host cells or foreign cells in an inflammatory milieu since immobilized proteins may expose Aβ-like structures after deposition at places where they are not supposed to be.
C 反应蛋白（CRP）与含有磷酸胆碱（PCh）的物质结合，随后激活补体系统以消除配体。从节肢动物到人类，CRP 的 PCh 结合功能在进化过程中得以保留。在酸性 pH 值下，CRP 的结构发生改变，也与淀粉样β（Aβ）结合，并阻止 Aβ 纤维的形成。目前尚不清楚 CRP 的 Aβ 结合功能是否也在进化中得到了保留。本研究旨在确定从美洲鲎分离出的 CRP 是否也具有抗淀粉样特性，以及该功能是否需要 CRP（Li-CRP）的结构改变。通过 PCh 亲和层析和磷酸乙醇胺亲和层析，分别从鲎血淋巴中纯化出两种 CRP 物种 Li-CRP-I 和 Li-CRP-II。Li-CRP-I 和 Li-CRP-II 均在生理 pH 值下与固定化 Aβ结合。与人类 CRP 不同，Li-CRP 无需发生任何结构变化即可与 Aβ结合。Li-CRP-I 和 Li-CRP-II 也在液相中与 Aβ结合，并阻止 Aβ 的纤维形成。此外，纯化的 Li-CRP 的离子交换层析表明，在血淋巴中存在各种具有不同亚基组成的 Li-CRP 分子，这增加了在血淋巴中存在各种 Li-CRP 物种的可能性，有助于识别具有不同淀粉样特性的一系列蛋白质。我们得出结论，CRP 与 Aβ 的结合是 CRP 的古老功能。在无脊椎动物中，CRP 的 Aβ 结合功能可以保护宿主免受由淀粉样和致病性蛋白引起的毒性。在人类中，CRP 的 Aβ 结合功能可以预防炎症性疾病，因为在炎症环境中，宿主蛋白会异位沉积在宿主细胞或外来细胞上，固定化的蛋白质在不应该存在的地方沉积后可能会暴露类似 Aβ 的结构。
