Interaction between the C8α-γ and C8β Subunits of Human Complement C8: Role of the C8β N-Terminal Thrombospondin Type 1 Module and Membrane Attack Complex/Perforin Domain

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Abstract
Human C8 is one of five complement components (C5b, C6, C7, C8, and C9) that interact to form the cytolytic membrane attack complex (MAC). It is an oligomeric protein composed of a disulfide-linked C8α-γ heterodimer and a noncovalently associated C8β chain. C8α and C8β are homologous; both contain an N-terminal thrombospondin type 1 (TSP1) module, a low-density lipoprotein receptor class A (LDLRA) module, an extended central segment referred to as the membrane attack/perforin (MACPF) domain, an epidermal growth factor (EGF) module, and a second TSP1 module at the C-terminus. In this study, the segment of C8β that confers binding specificity toward C8α-γ was identified using recombinant C8β constructs in which the N- and/or C-terminal modules were deleted or exchanged with those from C8α. Constructs were tested for their ability to bind C8α-γ in solution and express C8 hemolytic activity. Binding to C8α-γ was found to be dependent on the TSP1 + LDLRA + MACPF segment of C8β. Within this segment, the TSP1 module and MACPF domain are principally involved and act cooperatively to mediate binding. Results from activity assays suggest that residues within this segment also mediate binding and incorporation of C8 into the MAC.