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 HP Law, Susan M Ekkel, Stephanie C Kondos, Robert J A Goode, Georg Ramm, James C Whisstock, Helen R Saibil, Michelle A Dunstone

Research output: Contribution to journalArticleResearchpeer-review

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 A 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 beta-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.
Original languageEnglish
Article number10588
Number of pages6
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 4 Feb 2016

Cite this

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title = "Structure of the poly-C9 component of the complement membrane attack complex",
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 A 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 beta-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.",
author = "Dudkina, {Natalya V} and Spicer, {Bradley A} and Reboul, {Cyril F} and Conroy, {Paul J} and Natalya Lukoyanova and Hans Elmlund and Law, {Ruby HP} and Ekkel, {Susan M} and Kondos, {Stephanie C} and Goode, {Robert J A} and Georg Ramm and Whisstock, {James C} and Saibil, {Helen R} and Dunstone, {Michelle A}",
year = "2016",
month = "2",
day = "4",
doi = "10.1038/ncomms10588",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

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Structure of the poly-C9 component of the complement membrane attack complex. / Dudkina, Natalya V; Spicer, Bradley A; Reboul, Cyril F; Conroy, Paul J; Lukoyanova, Natalya; Elmlund, Hans; Law, Ruby HP; Ekkel, Susan M; Kondos, Stephanie C; Goode, Robert J A; Ramm, Georg; Whisstock, James C; Saibil, Helen R; Dunstone, Michelle A.

In: Nature Communications, Vol. 7, 10588, 04.02.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure of the poly-C9 component of the complement membrane attack complex

AU - Dudkina, Natalya V

AU - Spicer, Bradley A

AU - Reboul, Cyril F

AU - Conroy, Paul J

AU - Lukoyanova, Natalya

AU - Elmlund, Hans

AU - Law, Ruby HP

AU - Ekkel, Susan M

AU - Kondos, Stephanie C

AU - Goode, Robert J A

AU - Ramm, Georg

AU - Whisstock, James C

AU - Saibil, Helen R

AU - Dunstone, Michelle A

PY - 2016/2/4

Y1 - 2016/2/4

N2 - 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 A 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 beta-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.

AB - 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 A 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 beta-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.

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