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J Immunol. 2015 Nov 15;195(10):4986-98. doi: 10.4049/jimmunol.1501388. Epub 2015 Oct 12.

Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement.

Author information

1
School of Chemistry, University of Edinburgh, Edinburgh EH9 3FJ, United Kingdom;
2
School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom; and.
3
School of Chemistry, University of Edinburgh, Edinburgh EH9 3FJ, United Kingdom; Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
4
Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
5
School of Chemistry, University of Edinburgh, Edinburgh EH9 3FJ, United Kingdom; Paul.Barlow@ed.ac.uk A.Herbert@ed.ac.uk.

Abstract

In an attempt to evade annihilation by the vertebrate complement system, many microbes capture factor H (FH), the key soluble complement-regulating protein in human plasma. However, FH is normally an active complement suppressor exclusively on self-surfaces and this selective action of FH is pivotal to self versus non-self discrimination by the complement system. We investigated whether the bacterially captured FH becomes functionally enhanced and, if so, how this is achieved at a structural level. We found, using site-directed and truncation mutagenesis, surface plasmon resonance, nuclear magnetic resonance spectroscopy, and cross-linking and mass spectrometry, that the N-terminal domain of Streptococcus pneumoniae protein PspC (PspCN) not only binds FH extraordinarily tightly but also holds it in a previously uncharacterized conformation. Functional enhancement arises from exposure of a C-terminal cryptic second binding site in FH for C3b, the activation-specific fragment of the pivotal complement component, C3. This conformational change of FH doubles its affinity for C3b and increases 5-fold its ability to accelerate decay of the binary enzyme (C3bBb) responsible for converting C3 to C3b in an amplification loop. Despite not sharing critical FH-binding residues, PspCNs from D39 and Tigr4 S. pneumoniae exhibit similar FH-anchoring and enhancing properties. We propose that these bacterial proteins mimic molecular markers of self-surfaces, providing a compelling hypothesis for how FH prevents complement-mediated injury to host tissue while lacking efficacy on virtually all other surfaces. In hemolysis assays with 2-aminoethylisothiouronium bromide-treated erythrocytes that recapitulate paroxysmal nocturnal hemoglobinuria, PspCN enhanced protection of cells by FH, suggesting a new paradigm for therapeutic complement suppression.

PMID:
26459349
PMCID:
PMC4635569
DOI:
10.4049/jimmunol.1501388
[Indexed for MEDLINE]
Free PMC Article

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