Abstract
Complement component 9 (C9) functions as the pore-forming component of the Membrane Attack Complex (MAC). During MAC assembly, multiple copies of C9 are sequentially recruited to membrane associated C5b8 to form a pore. Here we determined the 2.2 Å crystal structure of monomeric murine C9 and the 3.9 Å resolution cryo EM structure of C9 in a polymeric assembly. Comparison with other MAC proteins reveals that the first transmembrane region (TMH1) in monomeric C9 is uniquely positioned and functions to inhibit its self-assembly in the absence of C5b8. We further show that following C9 recruitment to C5b8, a conformational change in TMH1 permits unidirectional and sequential binding of additional C9 monomers to the growing MAC. This mechanism of pore formation contrasts with related proteins, such as perforin and the cholesterol dependent cytolysins, where it is believed that pre-pore assembly occurs prior to the simultaneous release of the transmembrane regions.
Highlights
Complement component 9 (C9) functions as the pore-forming component of the Membrane Attack Complex (MAC)
The MAC is unusual in that it is initiated by a non-MACPF domain protein, C5b, which allows the sequential binding of single units of the MACPF-domain containing proteins C6, C7 and C8 complex (C8αβγ)
Once an individual component is associated with the nascent MAC, its elongation surface is activated such that it can interact with the binding surface of the soluble component to join the complex (Supplementary Fig 1)
Summary
Complement component 9 (C9) functions as the pore-forming component of the Membrane Attack Complex (MAC). We further show that following C9 recruitment to C5b8, a conformational change in TMH1 permits unidirectional and sequential binding of additional C9 monomers to the growing MAC This mechanism of pore formation contrasts with related proteins, such as perforin and the cholesterol dependent cytolysins, where it is believed that pre-pore assembly occurs prior to the simultaneous release of the transmembrane regions. The MAC is unusual in that it is initiated by a non-MACPF domain protein, C5b, which allows the sequential binding of single units of the MACPF-domain containing proteins C6, C7 and C8 complex (C8αβγ) This assembly (C5b8) allows the binding of multiple units of C9 that form the final ring-shaped pore (Supplementary Fig. 1a). The complete MAC contains ~18 C9-monomers in the full assembly
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