title: Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites.
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.
authors.affiliation: Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.|Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Braig
authors.affiliation: ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Nero
authors.affiliation: Institute for Biochemistry and Molecular Biology and Spemann-Graduate School for Biology and Medicine University of Freiburg, Medical Faculty of the University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Koch
authors.affiliation: Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Benedict
authors.initials: B
authors.lastname: Kaiser
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.|Departments of Medicine and Immunology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Jan R
authors.initials: JR
authors.lastname: Thiele
authors.affiliation: ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.affiliation: Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zeller
authors.affiliation: Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Jurij
authors.initials: J
authors.lastname: Kiefer
authors.affiliation: College of Pharmacy, Roosevelt University, Schaumburg, Illinois 60173, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Potempa
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Mellett
authors.affiliation: ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Miles
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.|Departments of Medicine and Immunology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Peter J
authors.identifier: 0000-0002-2593-4665
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: Department of Traumatology, Hand, Plastic, and Reconstructive Surgery, Center of Surgery, University of Ulm, 89081 Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
authors.affiliation: Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.
authors.forename: G Björn
authors.initials: GB
authors.lastname: Stark
authors.affiliation: ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Michael W
authors.identifier: 0000-0002-3101-1138
authors.initials: MW
authors.lastname: Parker
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.|Departments of Medicine and Immunology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
authors.affiliation: Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Steffen U
authors.initials: SU
authors.lastname: Eisenhardt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002097:C-Reactive Protein / Q000737:chemistry* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006586:Hexanes / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides; D008958:Models, Molecular; D009000:Monocytes / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats
chemical_list: C510236:1,6-bis(phosphocholine)-hexane; D006586:Hexanes; D008070:Lipopolysaccharides; D010767:Phosphorylcholine; D002097:C-Reactive Protein