Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate:: mCRPm
Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate:: mCRPm
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DOI：
10.1096/fj.06-6722com
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发表时间：
2007-01-01
期刊：
影响因子：
4.8
通讯作者：
Zhao, Jing
中科院分区：
文献类型：
--
作者：
Ji, Shang-Rong;Wu, Yi;Zhao, Jing
新出现的证据表明，C - 反应蛋白（CRP）至少有两种构象不同的异构体，即五聚体CRP（pCRP）和单体CRP（mCRP或CRP亚基）。两种CRP异构体都被认为在炎症中起作用，并可能参与心血管疾病的发病机制。然而，原位mCRP的来源以及在生理/病理情况下两种CRP异构体之间的相互作用仍然不清楚。在此，通过探测构象改变、新表位表达以及使用电子显微镜直接观察，我们发现pCRP与膜（包括脂质体和细胞膜）的钙依赖性结合导致了快速但部分的结构变化，产生了表达CRP亚基抗原性但保留天然五聚体构象的分子。这种杂合分子在此被称为mCRP（m）。mCRP（m）的形成与补体固定显著增强有关。mCRP（m）可以进一步从膜上脱离，形成在溶液中转化的、已被充分认识的mCRP异构体[mCRP（s）]，并对内皮细胞产生强大的刺激作用。膜诱导的pCRP解离不仅为mCRP的形成提供了一种生理相关的情形，而且可能代表了一种调节CRP功能的重要机制。
Emerging evidence indicates that C-reactive protein (CRP) has at least two conformationally distinct isoforms, i.e., pentameric CRP (pCRP) and monomeric CRP (mCRP or CRP subunit). Both CRP isoforms are proposed to play roles in inflammation and may participate in the pathogenesis of cardiovascular disease. However, the origin of mCRP in situ and the interplay between the two CRP isoforms under physiological/ pathological circumstances remain elusive. Herein, by probing conformational alteration, neoepitope expression, and direct visualization using electron-microscopy, we have shown that calcium-dependent binding of pCRP to membranes, including liposomes and cell membranes, led to a rapid but partial structural change, producing molecules that express CRP subunit antigenicity but with retained native pentameric conformation. This hybrid molecule is herein termed mCRP(m). The formation of mCRPm was associated with significantly enhanced complement fixation. mCRP(m) can further detach from membrane to form the well-recognized mCRP isoform converted in solution (mCRP(s)) and exert potent stimulatory effects on endothelial cells. The membrane-induced pCRP dissociation not only provides a physiologically relevant scenario for mCRP formation but may represent an important mechanism for regulating CRP function.