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Mol Cell Proteomics. 2016 Aug;15(8):2730-43. doi: 10.1074/mcp.M115.056473. Epub 2016 Jun 1.

Structure of Complement C3(H2O) Revealed By Quantitative Cross-Linking/Mass Spectrometry And Modeling.

Author information

  • 1From the ‡Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK;
  • 2§Unité de Bioinformatique Structurale, CNRS UMR 3528, Institut Pasteur, 75015 Paris, France; ¶Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Sciences, and California Institute for Quantitative Biomedical Sciences, University of California, San Francisco, California 94158, United States;
  • 3¶Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Sciences, and California Institute for Quantitative Biomedical Sciences, University of California, San Francisco, California 94158, United States;
  • 4§Unité de Bioinformatique Structurale, CNRS UMR 3528, Institut Pasteur, 75015 Paris, France;
  • 5‖Schools of Chemistry and Biological Sciences, University of Edinburgh, Edinburgh EH9 3JJ, UK; juri.rappsilber@ed.ac.uk paul.barlow@ed.ac.uk.
  • 6From the ‡Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK; **Chair of Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany juri.rappsilber@ed.ac.uk paul.barlow@ed.ac.uk.

Abstract

The slow but spontaneous and ubiquitous formation of C3(H2O), the hydrolytic and conformationally rearranged product of C3, initiates antibody-independent activation of the complement system that is a key first line of antimicrobial defense. The structure of C3(H2O) has not been determined. Here we subjected C3(H2O) to quantitative cross-linking/mass spectrometry (QCLMS). This revealed details of the structural differences and similarities between C3(H2O) and C3, as well as between C3(H2O) and its pivotal proteolytic cleavage product, C3b, which shares functionally similarity with C3(H2O). Considered in combination with the crystal structures of C3 and C3b, the QCMLS data suggest that C3(H2O) generation is accompanied by the migration of the thioester-containing domain of C3 from one end of the molecule to the other. This creates a stable C3b-like platform able to bind the zymogen, factor B, or the regulator, factor H. Integration of available crystallographic and QCLMS data allowed the determination of a 3D model of the C3(H2O) domain architecture. The unique arrangement of domains thus observed in C3(H2O), which retains the anaphylatoxin domain (that is excised when C3 is enzymatically activated to C3b), can be used to rationalize observed differences between C3(H2O) and C3b in terms of complement activation and regulation.

PMID:
27250206
PMCID:
PMC4974347
DOI:
10.1074/mcp.M115.056473
[PubMed - in process]
Free PMC Article
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