Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites

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 and Steffen U. Eisenhardt ()
Additional contact information
David Braig: University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg
Tracy L. Nero: ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research
Hans-Georg Koch: Institute for Biochemistry and Molecular Biology and Spemann-Graduate School for Biology and Medicine University of Freiburg, Medical Faculty of the University of Freiburg
Benedict Kaiser: University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg
Xiaowei Wang: Baker IDI Heart and Diabetes Institute
Jan R. Thiele: University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg
Craig J. Morton: ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research
Johannes Zeller: University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg
Jurij Kiefer: University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg
Lawrence A. Potempa: College of Pharmacy, Roosevelt University
Natalie A. Mellett: Baker IDI Heart and Diabetes Institute
Luke A. Miles: ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research
Xiao-Jun Du: Baker IDI Heart and Diabetes Institute
Peter J. Meikle: Baker IDI Heart and Diabetes Institute
Markus Huber-Lang: Hand, Plastic, and Reconstructive Surgery, Center of Surgery, University of Ulm
G. Björn Stark: University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg
Michael W. Parker: ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research
Karlheinz Peter: Baker IDI Heart and Diabetes Institute
Steffen U. Eisenhardt: University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14188

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