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Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP_m

Shang-Rong Ji^*, Yi Wu^*,1, Li Zhu^*, Lawrence A. Potempa, Fen-Ling Sheng, Wei Lu and Jing Zhao^*

^* MOE Key Laboratory of Arid and Grassland Ecology, Institute of Biophysics,

Instrumental Analysis Research Center, and

Institute of Cell Biology, Lanzhou University, Lanzhou, China; and

Immtech Pharmaceuticals Inc., Vernon Hills, Illinois, USA

¹Correspondence: Life Science Bldg., Rm. 227, Lanzhou University, Lanzhou 730000, China. E-mail: wuy{at}lzu.edu.cn

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 mCRP_m 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.—Shang-Rong Ji, Yi Wu, Li Zhu, Lawrence A. Potempa, Fen-Ling Sheng, Wei Lu, and Jing Zhao. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP_m.

Key Words: inflammation • cardiovascular disease • protein-membrane interaction