Complement C7 and clusterin form a complex in circulation
Mariam Massri1, Erik J M Toonen2, Bettina Sarg3
1Institute of Hygiene & Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Insights
Researchers discovered a new complex between complement protein C7 and clusterin in human blood. This finding suggests C7 has roles beyond its known function in the membrane attack complex, opening new avenues for complement system research.
Area of Science:
- Immunology
- Complement System
- Protein Interactions
Background:
- The complement system is crucial for innate immunity, host defense, and homeostasis.
- The membrane attack complex (MAC), formed by complement proteins, lyses pathogens.
- Complement protein C7 is essential for MAC assembly, but its inherent characteristics are understudied.
Purpose of the Study:
- To investigate the inherent molecular characteristics and protein-protein interactions of C7.
- To explore potential novel functions of C7 beyond its role in MAC formation.
Main Methods:
- Serum-purified C7 was analyzed using proteolytic methods, including Western blot and mass spectrometry.
- Protein-protein interactions were studied via enzyme-linked immunosorbent assay (ELISA) and size-exclusion chromatography.
- The presence of identified complexes was confirmed in healthy human serum and plasma donors.
Main Results:
- An association was identified between C7 and clusterin, a known complement regulator.
- A stable C7-clusterin (C7-CLU) complex was detected in purified C7, purified clusterin, and circulation.
- Clusterin was shown to bind to the native form of C7 in vivo.
Conclusions:
- C7 exhibits characteristics and interactions beyond its established role in MAC assembly.
- The C7-CLU complex exists in circulation, suggesting a potential in vivo function.
- Further research is warranted to elucidate the effector role of the C7-CLU complex in the complement cascade.
Introduction:
The complement system is part of innate immunity and is comprised of an intricate network of proteins that are vital for host defense and host homeostasis. A distinct mechanism by which complement defends against invading pathogens is through the membrane attack complex (MAC), a lytic structure that forms on target surfaces. The MAC is made up of several complement components, and one indispensable component of the MAC is C7. The role of C7 in MAC assembly is well documented, however, inherent characteristics of C7 are yet to be investigated.
Methods:
To shed light on the molecular characteristics of C7, we examined the properties of serum-purified C7 acquired using polyclonal and novel monoclonal antibodies. The properties of serum‑purified C7 were investigated through a series of proteolytic analyses, encompassing Western blot and mass spectrometry. The nature of C7 protein-protein interactions were further examined by a novel enzyme-linked immunosorbent assay (ELISA), as well as size‑exclusion chromatography.
Results:
Protein analyses showcased an association between C7 and clusterin, an inhibitory complement regulator. The distinct association between C7 and clusterin was also demonstrated in serum-purified clusterin. Further assessment revealed that a complex between C7 and clusterin (C7-CLU) was detected. The C7-CLU complex was also identified in healthy serum and plasma donors, highlighting the presence of the complex in circulation.
Discussion:
Clusterin is known to dissociate the MAC structure by binding to polymerized C9, nevertheless, here we show clusterin binding to the native form of a terminal complement protein in vivo. The presented data reveal that C7 exhibits characteristics beyond that of MAC assembly, instigating further investigation of the effector role that the C7-CLU complex plays in the complement cascade.
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