Title
Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites
Author
David Braig, Tracy L. Nero, Hans-Georg Koch, Benedict Kaiser, Xiaowei Wang, Jan R. Thiele, Craig J. Morton, Johannes Zeller, Jurij Kiefer, Lawrence A. Potempa, Natalie A. Mellett, Luke A. Miles, Xiao-Jun Du, Peter J. Meikle, Markus Huber-Lang, G. Björn Stark, Michael W. Parker, Karlheinz Peter, Steffen U. Eisenhardt
Year
2017
Journal
Nature Communications
Abstract
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.
Full Article
Instrument
J-815
Keywords
Circular dichroism, Secondary structure, Biochemistry