Structural basis and functional effects of the interaction between complement inhibitor C4b-binding protein and DNA
Marcin Okroj1, Huw T Jenkins, Andrew P Herbert
1Lund University, Department of Laboratory Medicine, Section of Medical Protein Chemistry, University Hospital Malmö, Malmö, Sweden.
Molecular Immunology
|August 22, 2008
Summary
Human C4b-binding protein (C4BP) binds DNA at its interdomain junction, a site also recognized by C4b and heparin. This interaction does not impede C4BP's crucial complement regulatory functions.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- Human C4b-binding protein (C4BP) is a key soluble inhibitor of the complement system.
- Previous studies indicated C4BP binds DNA, reducing its release from necrotic cells and limiting DNA-mediated complement activation.
- The precise binding mechanism and its impact on C4BP function were not fully understood.
Purpose of the Study:
- To elucidate the structural basis of DNA binding to C4BP.
- To investigate how DNA interaction affects C4BP's complement regulatory activities.
Main Methods:
- Nuclear magnetic resonance (NMR) spectroscopy was used to measure chemical shift perturbations.
- Computational docking was employed to model the interaction between DNA and C4BP domains 1-2 (C4BP12).
Main Results:
- NMR data identified six key residues (Val38, Ser40, Thr43, Tyr62, Lys63, Arg64) at the C4BP12 interdomain junction involved in DNA binding.
- The computational model revealed DNA binding in a cleft formed by the interdomain interface, with the double helix oriented perpendicular to the C4BP12 axis.
- DNA binding did not interfere with C4BP's cofactor activity for Factor I or its decay accelerating function for the classical C3 convertase.
- C4b and heparin, but not C3b, inhibited the DNA-C4BP interaction, suggesting a shared binding region.
Conclusions:
- C4BP utilizes specific residues at its interdomain junction to bind DNA, a region also recognized by C4b and heparin.
- This DNA interaction is likely multivalent, involving multiple C4BP arms, and does not compromise essential complement inhibitory functions.
- The findings support a model where C4BP can simultaneously interact with DNA/glycosaminoglycans and complement proteins like C4b/C3b.
Related Concept Videos
01:27Complement System
The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a membrane...
02:13Cooperative Binding of Transcription Regulators
Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome. Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form dimers that...
01:23Factors Affecting Protein-Drug Binding: Drug Interactions
Drug interactions are a critical aspect of pharmacology and can occur when two or more drugs compete for the same binding site. This competition can result in one drug displacing another, altering the effect of the displaced drug. Drug interactions are complex processes that rely heavily on how much of the displacer drug is present and how strongly it can bind to the same sites as the displaced drug.
Displacement interactions can have varying outcomes, ranging from toxicity to virtually...
Displacement interactions can have varying outcomes, ranging from toxicity to virtually...
01:26Antibody Actions
Antibodies, or immunoglobulins, are critical players in the immune system's arsenal against invading pathogens. Produced by B cells and plasma cells, their primary role is to detect and bind to specific antigens, molecules found on the surface of pathogens like bacteria or viruses. Beyond antigen recognition, antibodies perform several vital functions that contribute to immune defense.
Neutralization
Antibodies can bind to pathogens, preventing them from infecting host cells. This process...
Neutralization
Antibodies can bind to pathogens, preventing them from infecting host cells. This process...
00:49Ligand Binding and Linkage
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
01:23Antimicrobial Proteins
Antimicrobial proteins are important components of the immune system. They aid the body in combating pathogens by either killing them directly or hindering their replication processes. Four main types of antimicrobial substances are interferons, the complement system, iron-binding proteins, and antimicrobial proteins.
Interferons
Interferons (IFNs) are proteins produced by lymphocytes, macrophages, and fibroblasts infected with viruses. While IFNs cannot prevent viruses from entering and...
Interferons
Interferons (IFNs) are proteins produced by lymphocytes, macrophages, and fibroblasts infected with viruses. While IFNs cannot prevent viruses from entering and...