Allosteric inhibition of complement function by a staphylococcal immune evasion protein

The complement system is a major target of immune evasion by Staphylococcus aureus. Although many evasion proteins have been described, little is known about their molecular mechanisms of action. Here we demonstrate that the extracellular fibrinogen-binding protein (Efb) from S. aureus acts as an al...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 107; no. 41; pp. 17621 - 17626
Main Authors Chen, Hui, Ricklin, Daniel, Hammel, Michal, Garcia, Brandon L., McWhorter, William J., Sfyroera, Georgia, Wu, You-Qiang, Tzekou, Apostolia, Li, Sheng, Geisbrecht, Brian V., Woods, Virgil L., Lambris, John D.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 12.10.2010
National Acad Sciences
Subjects
Allosteric properties
Allosteric regulation
Allosteric Regulation - physiology
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Bacteriology
Binding sites
Biological Sciences
Complement activation
Complement C3-C5 Convertases - metabolism
Complement C3b - chemistry
Complement C3b - metabolism
Complement component C3
Complement component C3b
Complement factor B
Complement Factor B - metabolism
Complement Inactivator Proteins - chemistry
Complement Inactivator Proteins - metabolism
Crystal structure
Enzymes
Fibrinogen-binding protein
Immune evasion
Immune Evasion - physiology
Ligands
Mass Spectrometry
Mass spectroscopy
Medical treatment
Models, Molecular
Molecular chemistry
Molecular modelling
Protein Conformation
Proteins
Scattering, Small Angle
Staphylococcus
Staphylococcus aureus
Staphylococcus aureus - metabolism
Staphylococcus aureus - physiology
Staphylococcus infections
Surface Plasmon Resonance
Online AccessGet full text

Cover

More Information
Summary:The complement system is a major target of immune evasion by Staphylococcus aureus. Although many evasion proteins have been described, little is known about their molecular mechanisms of action. Here we demonstrate that the extracellular fibrinogen-binding protein (Efb) from S. aureus acts as an allosteric inhibitor by inducing conformational changes in complement fragment C3b that propagate across several domains and influence functional regions far distant from the Efb binding site. Most notably, the inhibitor impaired the interaction of C3b with complement factor B and, consequently, formation of the active C3 convertase. As this enzyme complex is critical for both activation and amplification of the complement response, its allosteric inhibition likely represents a fundamental contribution to the overall immune evasion strategy of S. aureus.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ObjectType-Article-2
ObjectType-Feature-1
1H.C. and D.R. contributed equally to this work; B.V.G., V.L.W., and J.D.L. contributed equally to this work.
Edited* by S. Walter Englander, University of Pennsylvania, Philadelphia, PA, and approved August 19, 2010 (received for review March 22, 2010)
Author contributions: H.C., D.R., B.V.G., V.L.W., and J.D.L. designed research; H.C., D.R., M.H., and S.L. performed research; B.L.G., W.J.M., G.S., Y.-Q.W., and A.T. contributed new reagents/analytic tools; H.C., D.R., M.H., B.V.G., V.L.W., and J.D.L. analyzed data; and H.C., D.R., M.H., B.V.G., and J.D.L. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1003750107