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Structural Basis for the Function of Complement Component C4 within the Classical and Lectin Pathways of Complement

Sofia Mortensen, Rune T. Kidmose, Steen V. Petersen, Ágnes Szilágyi, Zoltan Prohászka and Gregers R. Andersen
J Immunol April 24, 2015, 1500087; DOI: https://doi.org/10.4049/jimmunol.1500087
Sofia Mortensen
*Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark;
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Rune T. Kidmose
*Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark;
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Steen V. Petersen
†Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark; and
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Ágnes Szilágyi
‡3rd Department of Internal Medicine, Semmelweis University, Budapest 1125, Hungary
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Zoltan Prohászka
‡3rd Department of Internal Medicine, Semmelweis University, Budapest 1125, Hungary
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Gregers R. Andersen
*Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark;
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Abstract

Complement component C4 is a central protein in the classical and lectin pathways within the complement system. During activation of complement, its major fragment C4b becomes covalently attached to the surface of pathogens and altered self-tissue, where it acts as an opsonin marking the surface for removal. Moreover, C4b provides a platform for assembly of the proteolytically active convertases that mediate downstream complement activation by cleavage of C3 and C5. In this article, we present the crystal and solution structures of the 195-kDa C4b. Our results provide the molecular details of the rearrangement accompanying C4 cleavage and suggest intramolecular flexibility of C4b. The conformations of C4b and its paralogue C3b are shown to be remarkably conserved, suggesting that the convertases from the classical and alternative pathways are likely to share their overall architecture and mode of substrate recognition. We propose an overall molecular model for the classical pathway C5 convertase in complex with C5, suggesting that C3b increases the affinity for the substrate by inducing conformational changes in C4b rather than a direct interaction with C5. C4b-specific features revealed by our structural studies are probably involved in the assembly of the classical pathway C3/C5 convertases and C4b binding to regulators.

Footnotes

  • G.R.A. was supported by Alexion Pharmaceuticals, The Lundbeck Foundation Nanomedicine Centre for Individualized Management of Tissue Damage and Regeneration, and the Novo-Nordisk Foundation through a Hallas-Møller Fellowship. S.M. received a Boehringer-Ingelheim Fonds Ph.D. fellowship.

  • Coordinates and structure factors for the C4b crystal structure were deposited in the RCSB Protein Data Bank under accession code 4XAM.

  • The online version of this article contains supplemental material.

  • Received January 13, 2015.
  • Accepted March 22, 2015.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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Structural Basis for the Function of Complement Component C4 within the Classical and Lectin Pathways of Complement
Sofia Mortensen, Rune T. Kidmose, Steen V. Petersen, Ágnes Szilágyi, Zoltan Prohászka, Gregers R. Andersen
The Journal of Immunology April 24, 2015, 1500087; DOI: 10.4049/jimmunol.1500087

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Structural Basis for the Function of Complement Component C4 within the Classical and Lectin Pathways of Complement
Sofia Mortensen, Rune T. Kidmose, Steen V. Petersen, Ágnes Szilágyi, Zoltan Prohászka, Gregers R. Andersen
The Journal of Immunology April 24, 2015, 1500087; DOI: 10.4049/jimmunol.1500087
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Print ISSN 0022-1767        Online ISSN 1550-6606