Structure of the poly-C9 component of the complement membrane attack complex

Natalya V. Dudkina, Bradley A. Spicer, Cyril F. Reboul, Paul J. Conroy, Natalya Lukoyanova, Hans Elmlund, Ruby H. P. Law, Susan M. Ekkel, Stephanie C. Kondos, Robert J. A. Goode, Georg Ramm, James C. Whisstock (), Helen R. Saibil () and Michelle A. Dunstone ()
Additional contact information
Natalya V. Dudkina: Institute of Structural and Molecular Biology, Birkbeck College
Bradley A. Spicer: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
Cyril F. Reboul: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
Paul J. Conroy: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
Natalya Lukoyanova: Institute of Structural and Molecular Biology, Birkbeck College
Hans Elmlund: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
Ruby H. P. Law: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
Susan M. Ekkel: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
Stephanie C. Kondos: Biomedicine Discovery Institute, Clayton Campus, Monash University
Robert J. A. Goode: Biomedicine Discovery Institute, Clayton Campus, Monash University
Georg Ramm: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
James C. Whisstock: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University
Helen R. Saibil: Institute of Structural and Molecular Biology, Birkbeck College
Michelle A. Dunstone: ARC Centre of Excellence in Advanced Molecular Imaging, Clayton Campus, Monash University

Nature Communications, 2016, vol. 7, issue 1, 1-6

Abstract: Abstract The membrane attack complex (MAC)/perforin-like protein complement component 9 (C9) is the major component of the MAC, a multi-protein complex that forms pores in the membrane of target pathogens. In contrast to homologous proteins such as perforin and the cholesterol-dependent cytolysins (CDCs), all of which require the membrane for oligomerisation, C9 assembles directly onto the nascent MAC from solution. However, the molecular mechanism of MAC assembly remains to be understood. Here we present the 8 Å cryo-EM structure of a soluble form of the poly-C9 component of the MAC. These data reveal a 22-fold symmetrical arrangement of C9 molecules that yield an 88-strand pore-forming β-barrel. The N-terminal thrombospondin-1 (TSP1) domain forms an unexpectedly extensive part of the oligomerisation interface, thus likely facilitating solution-based assembly. These TSP1 interactions may also explain how additional C9 subunits can be recruited to the growing MAC subsequent to membrane insertion.

Date: 2016
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DOI: 10.1038/ncomms10588

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