Staphylococcal complement inhibitor: structure and active sites

Suzan H M Rooijakkers, Fin J Milder, Bart W Bardoel, Maartje Ruyken, Jos A G van Strijp, Piet Gros

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The pathogenic bacterium Staphylococcus aureus counteracts the host immune defense by excretion of the 85 residue staphylococcal complement inhibitor (SCIN). SCIN inhibits the central complement convertases; thereby, it reduces phagocytosis following opsonization and efficiently blocks all downstream effector functions. In this study, we present the crystal structure of SCIN at 1.8 A resolution and the identification of its active site. Functional characterization of structure based chimeric proteins, consisting of SCIN and the structurally but nonfunctional homologue open reading frame-D, indicate an 18-residue segment (Leu-31-Gly-48) crucial for SCIN activity. In all complement activation pathways, chimeras lacking these SCIN residues completely fail to inhibit production of the potent mediator of inflammation C5a. Inhibition of alternative pathway-mediated opsonization (C3b deposition) and formation of the lytic membrane attack complex (C5b-9 deposition) are strongly reduced for these chimeras as well. For inhibition of the classical/lectin pathway-mediated C3b and C5b-9 deposition, the same residues are critical although additional sites are involved. These chimeras also display reduced capacity to stabilize the C3 convertases of both the alternative and the classical/lectin pathway indicating the stabilizing effect is pivotal for the complement inhibitory activity of SCIN. Because SCIN specifically and efficiently inhibits complement, it has a high potential in anti-inflammatory therapy. Our data are a first step toward the development of a second generation molecule suitable for such therapeutic complement intervention.

Original languageEnglish
Pages (from-to)2989-98
Number of pages10
JournalJournal of Immunology
Volume179
Issue number5
DOIs
Publication statusPublished - 1 Sept 2007
Externally publishedYes

Keywords

  • amino acid sequence
  • bacterial proteins/chemistry
  • binding sites
  • complement C5a/antagonists & inhibitors
  • complement inactivator rroteins/chemistry
  • crystallography, x-ray
  • humans
  • molecular sequence data
  • protein conformation
  • recombinant fusion proteins/chemistry
  • staphylococcus aureus/immunology

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