The first transmembrane region of complement component-9 acts as a brake on its self-assembly

Bradley A. Spicer, Ruby H. P. Law, Tom T. Caradoc-Davies, Sue M. Ekkel, Charles Bayly-Jones, Siew-Siew Pang, Paul J. Conroy, Georg Ramm, Mazdak Radjainia, Hariprasad Venugopal, James C. Whisstock () and Michelle A. Dunstone ()
Additional contact information
Bradley A. Spicer: 23 Innovation Walk, Monash University
Ruby H. P. Law: 23 Innovation Walk, Monash University
Tom T. Caradoc-Davies: 23 Innovation Walk, Monash University
Sue M. Ekkel: 23 Innovation Walk, Monash University
Charles Bayly-Jones: 23 Innovation Walk, Monash University
Siew-Siew Pang: 23 Innovation Walk, Monash University
Paul J. Conroy: 23 Innovation Walk, Monash University
Georg Ramm: 23 Innovation Walk, Monash University
Mazdak Radjainia: Achtseweg Noord 5, Building
Hariprasad Venugopal: 23 Innovation Walk, Monash University
James C. Whisstock: 23 Innovation Walk, Monash University
Michelle A. Dunstone: 23 Innovation Walk, Monash University

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05717-0

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