Terminal complexes of the complement system: new structural insights and their relevance to function

Morgan, B. Paul; Walters, David; Serna, Marina; Bubeck, Doryen

doi:10.1111/imr.12461

Cited by 52 publications

(44 citation statements)

References 90 publications

(149 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, a direct and stable interaction between the C5 convertase and C5b6 may be needed to maintain a different conformation of C5b6 that is lost upon release of C5b6 from the surface. Although it has been postulated that C5b6 remains bound to the C5 convertase (Morgan et al , ), it is currently difficult to assess such complexes because of limited tools to study the multi‐component C5 convertase enzymes that have a surface‐specific conformation (Rawal & Pangburn, ). Please note that the structural models of (a subunit of the) C5 convertase enzyme bound to C5, C5b, and C5b6 (Fig A, B, CI and CII) are not experimentally proven.…”

Section: Discussionmentioning

confidence: 99%

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

et al. 2019

View full text Add to dashboard Cite

The immune system kills bacteria by the formation of lytic membrane attack complexes (MACs), triggered when complement enzymes cleave C5. At present, it is not understood how the MAC perturbs the composite cell envelope of Gram‐negative bacteria. Here, we show that the role of C5 convertase enzymes in MAC assembly extends beyond the cleavage of C5 into the MAC precursor C5b. Although purified MAC complexes generated from preassembled C5b6 perforate artificial lipid membranes and mammalian cells, these components lack bactericidal activity. In order to permeabilize both the bacterial outer and inner membrane and thus kill a bacterium, MACs need to be assembled locally by the C5 convertase enzymes. Our data indicate that C5b6 rapidly loses the capacity to form bactericidal pores; therefore, bacterial killing requires both in situ conversion of C5 and immediate insertion of C5b67 into the membrane. Using flow cytometry and atomic force microscopy, we show that local assembly of C5b6 at the bacterial surface is required for the efficient insertion of MAC pores into bacterial membranes. These studies provide basic molecular insights into MAC assembly and bacterial killing by the immune system.

show abstract

Section: Discussionmentioning

confidence: 99%

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The complement and coagulation cascades were identified as a common KEGG immune pathway enriched in deiminated proteins in cow serum and serum-EVs. The complement system bridges innate and adaptive immunity, has roles in clearing apoptotic and necrotic cells and is in the front line for clearing invading pathogens [115][116][117][118][119]. Dysregulation of the complement system is furthermore associated with a range of pathologies [120].…”

Section: Discussionmentioning

confidence: 99%

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

Criscitiello

Kraev

Lange

2020

IJMS

View full text Add to dashboard Cite

The bovine immune system is known for its unusual traits relating to immunoglobulin and antiviral responses. Peptidylarginine deiminases (PADs) are phylogenetically conserved enzymes that cause post-translational deimination, contributing to protein moonlighting in health and disease. PADs also regulate extracellular vesicle (EV) release, forming a critical part of cellular communication. As PAD-mediated mechanisms in bovine immunology and physiology remain to be investigated, this study profiled deimination signatures in serum and serum-EVs in Bos taurus. Bos EVs were poly-dispersed in a 70-500 nm size range and showed differences in deiminated protein cargo, compared with whole sera. Key immune, metabolic and gene regulatory proteins were identified to be post-translationally deiminated with some overlapping hits in sera and EVs (e.g., immunoglobulins), while some were unique to either serum or serum-EVs (e.g., histones). Protein-protein interaction network analysis of deiminated proteins revealed KEGG pathways common for serum and serum-EVs, including complement and coagulation cascades, viral infection (enveloped viruses), viral myocarditis, bacterial and parasitic infections, autoimmune disease, immunodeficiency intestinal IgA production, B-cell receptor signalling, natural killer cell mediated cytotoxicity, platelet activation and hematopoiesis, alongside metabolic pathways including ferroptosis, vitamin digestion and absorption, cholesterol metabolism and mineral absorption. KEGG pathways specific to EVs related to HIF-1 signalling, oestrogen signalling and biosynthesis of amino acids. KEGG pathways specific for serum only, related to Epstein-Barr virus infection, transcription mis-regulation in cancer, bladder cancer, Rap1 signalling pathway, calcium signalling pathway and ECM-receptor interaction. This indicates differences in physiological and pathological pathways for deiminated proteins in serum-EVs, compared with serum. Our findings may shed light on pathways underlying a number of pathological and anti-pathogenic (viral, bacterial, parasitic) pathways, with putative translatable value to human pathologies, zoonotic diseases and development of therapies for infections, including anti-viral therapies.

show abstract

“…Several molecules of C9 are incorporated to this complex creating a channel through the membrane (C5b6789 n ). This channel is a lytic pore leading to flow of water and ions which culminates in osmotic unbalance and the cell rupture (Morgan et al, 2016). When in solution, the C5b67 complex binds to the regulatory S-protein (also called Vitronectin) forming the complex (SC5b67).…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Leptospira Secreted Proteases Target the Membrane Attack Complex: A Potential Role for Thermolysin in Complement Inhibition

et al. 2017

View full text Add to dashboard Cite

Leptospirosis is a zoonosis caused by spirochetes from the genus Leptospira. This disease is common in tropical and subtropical areas, constituting a serious public health problem. Pathogenic Leptospira have the ability to escape the human Complement System, being able to survive when in contact with normal human serum. In a previous study, our group demonstrated that supernatants of pathogenic Leptospira (SPL) inhibit the three activation pathways of the Complement System. This inhibition can be directly correlated with the activity of secreted proteases, which cleave the Complement molecules C3, Factor B (Alternative Pathway), C4 and C2 (Classical and Lectin Pathways). In this work, we analyze the activity of the leptospiral proteases on the components of Terminal Pathway of Complement, called the membrane attack complex (MAC). We observed that proteases present in SPL from different Leptospira strains were able to cleave the purified proteins C5, C6, C7, C8, and C9, while culture supernatant from non-pathogenic Leptospira strains (SNPL) had no significant proteolytic activity on these substrates. The cleavages occurred in a time-dependent and specificity manner. No cleavage was observed when we used whole serum as a source of C5–C9 proteins, probably because of the abundant presence of plasma protease inhibitors such as α2-macroglobulin. Complement protein cleavage by SPL was inhibited by 1,10-phenanthroline, indicating the involvement of metalloproteases. Furthermore, 1,10-phenanthroline- treated normal human serum diminished pathogenic leptospira survival. We also analyzed the proteolytic activity of thermolysin (LIC13322) a metalloprotease expressed exclusively by pathogenic Leptospira strains. Recombinant thermolysin was capable of cleaving the component C6, either purified or as part of the SC5b-9 complex. Furthermore, we found that the MAC proteins C6–C9 interact with thermolysin, indicating that this metalloprotease may have an additional inhibitory effect on these molecules by direct interactions. Finally, a functional assay demonstrated that thermolysin was able to inhibit MAC-dependent erythrocytes lysis. We conclude that proteases secreted exclusively by pathogenic Leptospira strains are capable of degrading several Complement effector molecules, representing potential targets for the development of new therapies and prophylactic approaches in leptospirosis.

show abstract

Terminal complexes of the complement system: new structural insights and their relevance to function

Cited by 52 publications

References 90 publications

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

Pathogenic Leptospira Secreted Proteases Target the Membrane Attack Complex: A Potential Role for Thermolysin in Complement Inhibition

Contact Info

Product

Resources

About