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, Z. Prohászka, Gregers R. Andersen

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 selftissue, 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.

Original languageEnglish
Pages (from-to)5488-5496
Number of pages9
JournalJournal of Immunology
Volume194
Issue number11
DOIs
Publication statusPublished - Jun 1 2015

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Mannose-Binding Lectin Complement Pathway
Classical Complement Pathway
Complement C4
Complement Activation
Classical Pathway Complement C3-C5 Convertases
Classical Pathway Complement C5 Convertase
Opsonin Proteins
Molecular Models
Proteins

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Structural basis for the function of complement component C4 within the classical and lectin pathways of complement. / Mortensen, Sofia; Kidmose, Rune T.; Petersen, Steen V.; Szilágyi, Ágnes; Prohászka, Z.; Andersen, Gregers R.

In: Journal of Immunology, Vol. 194, No. 11, 01.06.2015, p. 5488-5496.

Research output: Contribution to journalArticle

Mortensen, Sofia ; Kidmose, Rune T. ; Petersen, Steen V. ; Szilágyi, Ágnes ; Prohászka, Z. ; Andersen, Gregers R. / Structural basis for the function of complement component C4 within the classical and lectin pathways of complement. In: Journal of Immunology. 2015 ; Vol. 194, No. 11. pp. 5488-5496.
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