Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites.
Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites.
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CRP结构的过渡变化导致促炎结合位点的暴露。
DOI：
10.1038/ncomms14188
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发表时间：
2017-01-23
影响因子：
16.6
通讯作者：
Eisenhardt SU
中科院分区：
文献类型：
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作者：
Braig D;Nero TL;Koch HG;Kaiser B;Wang X;Thiele JR;Morton CJ;Zeller J;Kiefer J;Potempa LA;Mellett NA;Miles LA;Du XJ;Meikle PJ;Huber-Lang M;Stark GB;Parker MW;Peter K;Eisenhardt SU
c反应蛋白（CRP）浓度在组织损伤或感染时升高。循环五聚体CRP （pCRP）定位于受损组织，导致补体活化和进一步的组织损伤。深入了解pCRP激活机制对于制定治疗策略以减少组织损伤至关重要。在这里，我们证明pCRP通过结合细胞来源的微泡经历结构变化而不破坏五聚体对称性（pCRP*）。pCRP*是人类炎症组织中主要的CRP种类，可结合补体因子1q （C1q）并激活经典补体途径。pCRP* -微泡复合物导致白细胞向炎症组织的募集增强。pCRP的一种小分子抑制剂（1,6-二（磷酸胆碱）-己烷）阻断了pCRP与微囊泡的相互作用，从而消除了这些促炎作用。通过治疗性抑制减少炎症介导的组织损伤可能改善心肌梗死、中风和其他炎症状况的预后。c反应蛋白是一种五聚体蛋白，由肝脏对损伤和感染作出反应而分泌。在这里，Braig等人表明，单核细胞来源的微泡表面的CRP构象变化使补体C1q结合，并导致补体级联的激活和炎症的加重。
C-reactive protein (CRP) concentrations rise in response to tissue injury or infection. Circulating pentameric CRP (pCRP) localizes to damaged tissue where it leads to complement activation and further tissue damage. In-depth knowledge of the pCRP activation mechanism is essential to develop therapeutic strategies to minimize tissue injury. Here we demonstrate that pCRP by binding to cell-derived microvesicles undergoes a structural change without disrupting the pentameric symmetry (pCRP*). pCRP* constitutes the major CRP species in human-inflamed tissue and allows binding of complement factor 1q (C1q) and activation of the classical complement pathway. pCRP*–microvesicle complexes lead to enhanced recruitment of leukocytes to inflamed tissue. A small-molecule inhibitor of pCRP (1,6-bis(phosphocholine)-hexane), which blocks the pCRP–microvesicle interactions, abrogates these proinflammatory effects. Reducing inflammation-mediated tissue injury by therapeutic inhibition might improve the outcome of myocardial infarction, stroke and other inflammatory conditions. C-reactive protein is a pentameric protein secreted by the liver in response to injury and infection. Here Braig et al. show that conformational changes in CRP on the surface of monocyte-derived microvesicles enable binding of complement C1q and lead to activation of the complement cascade and aggravation of inflammation.