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

• DOI: 10.1038/s41467-018-05717-0
• Publication Date: 2018-08-09T11:30:29Z
• Authors: Bradley A. Spicer; Ruby H. P. Law; Tom T. Caradoc-Da...; Sue M. Ekkel; Charles Bayly-Jones; Siew-Siew Pang; Paul J. Conroy; Georg Ramm; Mazdak Radjainia; Hariprasad Venugopal; James C. Whisstock; Michelle A. Dunstone
• Keywords: Models, Molecular; 0301 basic medicine; Science; Q; Cryoelectron Microscopy; Membrane Proteins; Complement Membrane Attack Complex; Complement System Proteins; Complement C9; Crystallography, X-Ray; Article; Mice; 03 medical and health sciences; Protein Domains; Animals; Humans; Protein Binding

AbstractComplement 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.