Complement: Terminal Pathways

Abstract

A central event in the complement activation is the cleavage of C5 by C5 convertases to form C5a and C5b. Nascent C5b can join sequentially with C6 through C9, and the assembly may proceed through one of the two pathways. If occurring near a phospholipid membrane, the membrane attack complex is formed; this is a circular transmembrane pore of 100 Å. If distal from a membrane, the late acting complement proteins associate with vitronectin and clusterin‐high density lipoprotein generating soluble complexes collectively referred to as SC5b‐9. Advancements in X‐ray crystallography and electron microscopy have revealed as to how the monomers transform in conformation to become protomers in the polymers. Components C6 through C9 contain a central domain (MACPF) flanked and extended by cysteine‐rich modules that perform binding functions and hold the monomers in a state of potentiation. Upon joining with C5b, several modules displace enabling assembly. Experimental evidence has suggested that the folding of subunits within the MAC is inverted to that of the bacterial cholesterol‐dependent cytolysins. Key Concepts: Complement C6 through C9 consist of a single central domain, the MACPF, flanked by auxiliary modules related to those found in thrombospondin, the LDL receptor, the epidermal growth factor, complement control proteins and factor I. In their soluble monomer state the terminal components of complement (C6 through C9) are held in a state of potentiation by their auxiliary modules, which get displaced in the process of subunit association, thereby exposing their core β‐sheets enabling protomer association in the polymer. The terminal components of complement through their MACPF domains share a similar tertiary structure to the equivalent domains of the bacterial cholesterol‐dependent cytolysins (CDCs), yet little to no sequence homology is evident between the vertebrate MACPFs and the analogous bacterial domains. Although similar in tertiary structure, perforin (and probably the components of the MAC) fold within their respective polymers in a manner inverted to those of the bacterial CDCs. Heterogeneity characterises the soluble terminal complement complexes (SC5b‐9) as these are associated with vitronectin, clusterin and lipoprotein. The soluble terminal complement complexes may function in vivo for clearance and wound healing.