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

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....

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Bibliographic Details
Published in:	Nature communications 2018-08, Vol.9 (1), p.3266-7, Article 3266
Main Authors:	Spicer, Bradley A, Law, Ruby H P, Caradoc-Davies, Tom T, Ekkel, Sue M, Bayly-Jones, Charles, Pang, Siew-Siew, Conroy, Paul J, Ramm, Georg, Radjainia, Mazdak, Venugopal, Hariprasad, Whisstock, James C, Dunstone, Michelle A
Format:	Article
Language:	eng
Subjects:	Animals Biochemistry Cholesterol Complement C9 - chemistry Complement C9 - genetics Complement C9 - metabolism Complement component C9 Complement Membrane Attack Complex - chemistry Complement Membrane Attack Complex - metabolism Complement Membrane Attack Complex - ultrastructure Complement System Proteins - chemistry Complement System Proteins - genetics Complement System Proteins - metabolism Cryoelectron Microscopy Crystal structure Crystallography, X-Ray Cytolysins Epidermal growth factor Humans Low density lipoprotein receptors Membrane attack complex Membrane Proteins - chemistry Membrane Proteins - genetics Membrane Proteins - metabolism Mice Models, Molecular Molecular biology Monomers Perforin Pore formation Protein Binding Protein Domains Proteins Self assembly
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Summary:	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.
ISSN:	2041-1723 2041-1723