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

Author

Listed:
  • David Braig

    (University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg
    Baker IDI Heart and Diabetes Institute)

  • 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
    Monash University)

  • 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
    Bio21 Molecular Science and Biotechnology Institute, University of Melbourne)

  • Xiao-Jun Du

    (Baker IDI Heart and Diabetes Institute
    Monash University)

  • Peter J. Meikle

    (Baker IDI Heart and Diabetes Institute
    Bio21 Molecular Science and Biotechnology Institute, University of Melbourne)

  • 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
    Bio21 Molecular Science and Biotechnology Institute, University of Melbourne)

  • Karlheinz Peter

    (Baker IDI Heart and Diabetes Institute
    Monash University)

  • Steffen U. Eisenhardt

    (University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg)

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.

Suggested Citation

  • 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. M, 2017. "Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites," Nature Communications, Nature, vol. 8(1), pages 1-19, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14188
    DOI: 10.1038/ncomms14188
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    Cited by:

    1. Hongwei Lu & An Chen & Xindan Zhang & Zixiang Wei & Rong Cao & Yi Zhu & Jingxiong Lu & Zhongling Wang & Leilei Tian, 2022. "A pH-responsive T1-T2 dual-modal MRI contrast agent for cancer imaging," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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