Redox Regulation Of The Structure And Function Of C-reactive Protein

C-reactive protein (CRP) is the prototypical human acute phase reactant that is primiarly produced and metabolized by the liver. In addition to being the most widely used non-specific marker of inflammation in the clinical practice, recent evidence indicates that CRP is also an predictor of cardiovascular disease. Moreover, CRP may also participate into the underlying inflammatory processes of atherosclerosis and thrombosis. CRP has at least two isoforms, i.e. pentameric CRP (pCRP) composed of five identical subunits and monomeric CRP (mCRP) that is probably generated by dissociation of pCRP in inflammatory loci. pCRP appears to exert primarily anti-inflammatory actions, while we and others have revealed potent pro-inflammatory activities of mCRP. However, little is known about the molecular mechanisms that controls the generation and functions of mCRP. Herein, we found pCRP could be rapidly converted to mCRP with the presence of mild acidic pH and reactive oxygen species, two conditions that are frequently exist in inflammatory lesions. We further identified Cys36as a conserved sulfur switch that regualtes the endothelial cell stimulating capacity of mCRP. Cys36forms the intra-subunit disulfide bond with Cys97in pCRP. Conformational rearrangement to mCRP is the prerequisite for the disulfide bond to be accessible by physiological reductants, including thioredoxin, GSH and Cys. Immunohistochemical analysis revealed36-79%co-localization of thioredoxin and mCRP in human advanced coronary atherosclerotic lesions. Non-reduced mCRP was largely inert in activating endothelial cells, whereas reduction of the disulfide bond or muating the cysteine residues transformed mCRP to a potent endothelial activator. These actions were primarily due to the unlocking of the lipid raft interaction motif containing the sulfur switch Cys36. Therefore, expression of pro-inflammatory properties of CRP on endothelial cells requires sequential conformational changes, i.e. loss of pentameric symmetry followed by reduction of the intra-subunit disulfide bond.