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Interaction of Shiga toxin 2 with complement regulators of the factor H protein family.

Abstract
Shiga toxin 2 (Stx2) is believed to be a major virulence factor of enterohemorrhagic Escherichia coli (EHEC) contributing to hemolytic uremic syndrome (HUS). The complement system has recently been found to be involved in the pathogenesis of EHEC-associated HUS. Stx2 was shown to activate complement via the alternative pathway, to bind factor H (FH) at short consensus repeats (SCRs) 6-8 and 18-20 and to delay and reduce FH cofactor activity on the cell surface. We now show that complement factor H-related protein 1 (FHR-1) and factor H-like protein 1 (FHL-1), proteins of the FH protein family that show amino acid sequence and regulatory function similarities with FH, also bind to Stx2. The FHR-1 binding site for Stx2 was located at SCRs 3-5 and the binding capacity of FHR-1*A allotype was higher than that of FHR-1*B. FHR-1 and FHL-1 competed with FH for Stx2 binding, and in the case of FHR-1 this competition resulted in a reduction of FH cofactor activity. FHL-1 retained its cofactor activity in the fluid phase when bound to Stx2. In conclusion, multiple interactions of key complement inhibitors FH, FHR-1 and FHL-1 with Stx2 corroborate our hypothesis of a direct role of complement in EHEC-associated HUS.
AuthorsKulwara Poolpol, Dorothea Orth-Höller, Cornelia Speth, Peter F Zipfel, Christine Skerka, Santiago Rodriguez de Córdoba, Jens Brockmeyer, Martina Bielaszewska, Reinhard Würzner
JournalMolecular immunology (Mol Immunol) Vol. 58 Issue 1 Pg. 77-84 (Mar 2014) ISSN: 1872-9142 [Electronic] England
PMID24317278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Blood Proteins
  • CFHR1 protein, human
  • Complement C3b Inactivator Proteins
  • Shiga Toxin 2
  • factor H-related protein 1
  • Complement Factor H
Topics
  • Amino Acid Sequence
  • Binding Sites
  • Blood Proteins (genetics, immunology)
  • Complement C3b Inactivator Proteins (genetics, immunology)
  • Complement Factor H (genetics, immunology)
  • Enterohemorrhagic Escherichia coli (pathogenicity)
  • Escherichia coli Infections (immunology, microbiology, pathology)
  • Hemolytic-Uremic Syndrome (immunology, microbiology, pathology)
  • Humans
  • Protein Binding (immunology)
  • Shiga Toxin 2 (immunology)

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