A common site within factor H SCR 7 responsible for binding heparin, C‐reactive protein and streptococcal M protein
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The complement inhibitor factor H (fH) interacts via its seventh short consensus repeat (SCR) domain with multiple ligands including heparin, streptococcal M protein and C‐reactive protein (CRP). The aim of this study was to localize the residues in SCR 7 required for these interactions. We initially built a homology model of fH SCR 6–7 using the averaged NMR structures of fH SCR 15–16 and vaccinia control protein SCR 3–4 as templates. Electrostatic potentials of the model's surface demonstrated a co‐localization of three clusters of positively charged residues on SCR 7, labeled site A (R369 and K370), site B (R386 and K387) and site C (K392). These residues, localized to the linker region preceding SCR 7 and to the end of a "hypervariable loop" in SCR 7, were systematically replaced with uncharged alanine residues in an fH construct containing SCR 1–7. The resulting proteins were expressed in the methylotrophic yeast, Pichia pastoris. By ELISA analysis we demonstrated: first, that substituting site A inhibited heparin and CRP binding; secondly, that substituting site B inhibited binding to heparin, CRP and M protein; and thirdly, that substituting site C clearly inhibited only heparin binding.
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Soft drusen are comprised, in part, of complement proteins including CFH and its binding partner, complement 3b.
“This observation may not be surprising given that soft drusen is comprised, in part, of complement proteins including CFH and its binding partner, complement 3b [20].”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [20]
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- Authors
- Giannakis, E., Jokiranta, T. S., Male, D. A., Ranganathan, S., Ormsby, R. J., Fischetti, V. A., Mold, C., & Gordon, D. L.
- Affiliations
- Flinders Medical Centre (AU)
- Helsinki University Hospital (FI)
- National University of Singapore (SG)
- University of New Mexico (US)
- Corresponding author
- Gordon, David L.
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2003-03-18
- Volume
- 33
- Issue
- 4
- Pages
- 962-969
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W2018133348
- Cited by
- 166
- References
- 56
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 7 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 8 · 2012: 9
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Flinders Academic Commons (Flinders University) (submittedVersion)
- Funders
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Academy of Finland
- Medical Research Council
- National Health and Medical Research Council (160030)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Keywords
- complement factor H, complement inhibitors, heparin binding, streptococcal M protein, ligand binding sites, hypervariable loops, complement regulation, site-directed mutagenesis, Pichia pastoris expression
- MeSH terms
- Antigens, Bacterial, Bacterial Outer Membrane Proteins, Binding Sites, C-Reactive Protein, Carrier Proteins, Heparin, Humans, Models, Molecular, Mutagenesis, Site-Directed, Complement Factor H, Protein Structure, Tertiary, Amino Acid Substitution, Repetitive Sequences, Amino Acid, Structural Homology, Protein
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