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

Bradley A. Spicer, Ruby H.P. Law, Thomas T. Caradoc-Davies, Sue M. Ekkel, Charles Bayly-Jones, Siew-Siew Pang, Paul J. Conroy, Georg Ramm, Mazdak Radjainia, Hariprasad Venugopal, James C. Whisstock, Michelle A. Dunstone

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Article number3266
Number of pages7
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 15 Aug 2018

Keywords

  • biochemistry
  • complement cascade
  • electron microscopy
  • immunology
  • structural biology

Cite this

@article{31d8bab12ada4076bb2e947efd3395cc,
title = "The first transmembrane region of complement component-9 acts as a brake on its self-assembly",
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 {\AA} crystal structure of monomeric murine C9 and the 3.9 {\AA} 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.",
keywords = "biochemistry, complement cascade, electron microscopy, immunology, structural biology",
author = "Spicer, {Bradley A.} and Law, {Ruby H.P.} and Caradoc-Davies, {Thomas T.} and Ekkel, {Sue M.} and Charles Bayly-Jones and Siew-Siew Pang and Conroy, {Paul J.} and Georg Ramm and Mazdak Radjainia and Hariprasad Venugopal and Whisstock, {James C.} and Dunstone, {Michelle A.}",
year = "2018",
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doi = "10.1038/s41467-018-05717-0",
language = "English",
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The first transmembrane region of complement component-9 acts as a brake on its self-assembly. / Spicer, Bradley A.; Law, Ruby H.P.; Caradoc-Davies, Thomas 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.

In: Nature Communications, Vol. 9, No. 1, 3266, 15.08.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - The first transmembrane region of complement component-9 acts as a brake on its self-assembly

AU - Spicer, Bradley A.

AU - Law, Ruby H.P.

AU - Caradoc-Davies, Thomas T.

AU - Ekkel, Sue M.

AU - Bayly-Jones, Charles

AU - Pang, Siew-Siew

AU - Conroy, Paul J.

AU - Ramm, Georg

AU - Radjainia, Mazdak

AU - Venugopal, Hariprasad

AU - Whisstock, James C.

AU - Dunstone, Michelle A.

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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.

AB - 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.

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