The complement system is an ancient component of vertebrate immune defense. One major end point of complement activation is the formation of the membrane attack complex (MAC), which is a circular multiprotein assembly that can embed into a phospholipid membrane of a target cell generating a large pore. Deficiencies in any of the MAC components cause enhanced susceptibility to Gram-negative bacterial infections such as those caused by Neisseria meningitidis.
The mature MAC includes single copies of C5b, C6, and C7 and the heterotrimeric C8αβγ complex and 12-18 copies of C9. All MAC components, except C5b and C8γ (a small protein attached to the side of C8α), contain a homologous central region of ∼350 amino acids termed the membrane attack complex-perforin (MACPF) domain.
Complement component C6 is the longest of the MAC proteins. In its monomeric form, it is a single chain plasma glycoprotein of Mr ∼106,000, consisting of 913 residues folded as nine auxiliary/regulatory domains complementing the MACPF core. Although the precise functions of the auxiliary domains are unclear, their importance in membrane attack complex (MAC) assembly is supported by several studies. For example, two independent studies (using deletion mutants) demonstrated that the N-terminal modules of C8α (TS2 and LR) are strictly required for MACPF formation and hemolytic activity, although deletion of the C-terminal TS3 domain greatly reduced activity.
The crystal structure of full-length complement C6 described by Alexander et al. was at 2.85 Å resolution. Comparisons with the structures of the C8αβγ heterodimer and perforin show that the central domain of complement C6 adopts a "closed" (perforin-like) state that is distinct from the "open" conformations in complement C8.
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