C8

Background

As is known to all, the complement system can lyse the target cells by forming the membrane attack complex (MAC) on the surface of pathogen cell membranes. The MAC is a large poroid protein complex consisting of complement C5b, C6, C7, C8, and C9. Complement component 8 (C8) is a ~150 kDa glycosylated heterotrimer protein composed of 3 polypeptide chains: α chain, β chain, and γ chain, namely C8A, C8B, and C8G, respectively. The α chain and β chain are noncovalently held together, and the γ chain binds to the α chain by a disulfide bond. The α chain and the β chain are highly homologous to C6, C7, and C9, which contain a MAC perforin domain and several other modules, whereas, the γ chain is a single domain polypeptide with a lipocalin fold. The α chain and β chain of C8 play essential roles in the formation of MAC. The MAC perforin domain in the β chain is responsible for integrating C8 with the previously formed C5b-7 complex. Once the C8B is bound to C5b-7, the MAC perforin domain of the α chain undergoes a conformational change to insert into the membrane and also serves as the binding site of C9 to form MAC. C8 is also a critical component of the soluble terminal complex component sC5b-9.

C8 deficiency is usually caused by mutations in the C8A or C8B gene, leading to an increased risk of recurrent bacterial infections, especially neisserial infections, and immunodeficiency.

Fig.1 Structural organization of the human complement component C8 complex.Distributed under CC BY-SA 3.0, from Wiki, without modification.

C8 Functional Service

Creative Biolabs provides a diverse range of C8-related products, such as anti-C8 antibodies and recombinant C8 proteins. These carefully designed reagents play a crucial role in propelling research focused on devising therapeutic approaches for numerous diseases.

Fig.2 Impact of membrane context on MAC formation and suppression.¹

CD59, a key immuno-regulatory receptor, safeguards human cells by inhibiting complement activation damage. Scientists have delineated the mechanism through which CD59 interacts with complement proteins C8 and C9 on the membrane interface, thereby hindering the formation and assembly of MAC pores. Through cryo-electron microscopy, structures of two inhibited MAC precursors, C5b8 and C5b9, are presented. In these complexes, CD59 interacts with the pore-forming β-hairpins of C8, forming an intermolecular β-sheet that deters membrane perforation. Concurrently, CD59 influences C9 β-hairpins, redirecting them away from the membrane, thereby preventing their integration and halting MAC polymerization. This structural and functional insight is further complemented by cellular assays and molecular dynamics simulations, elucidating the influence of the membrane environment on CD59’s dual role in MAC pore regulation and as a target for bacterial virulence factors exploiting CD59 to lyse human cells.

Creative Biolabs provides a diverse array of customized C8-functional services, encompassing detailed interaction analyses and supplementary functional features. These meticulously tailored offerings are crafted to support our clients in furthering their prominent scientific research and clinical pursuits.

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Reference

1. Couves, Emma C., et al. "Structural basis for membrane attack complex inhibition by CD59." Nature Communications 14.1 (2023): 890. Distributed under Open Access license CC BY 4.0, without modification.