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 Anne

doi:10.1038/s41467-018-05717-0

Cited by 55 publications

(72 citation statements)

References 50 publications

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“…Interestingly, the rate-limiting step of MAC assembly, as identified here, coincides with unfurling of the first C9's hairpins into the membrane. This can be related to the recent structural insight that C9 can bind to the C5b-8 initiator complex before inserting into the membrane; however, undergoing the helix-to-hairpin transition is required to propagate oligomerization 15 .…”

Section: Discussionmentioning

confidence: 88%

“…Recruitment of C7 unfurls a lipophilic domain upon binding, while integration of C8 into the assembly is accompanied by an initial insertion into the membrane. The C5b-8 initiator complex then binds C9 and undergoes unidirectional oligomerization (with 18 copies of C9) to complete an 11 nm wide transmembrane pore, as characterized in increasing structural detail by cryo-electron microscopy (cryoEM) [12][13][14][15][16] . Together with crystallographic structures of component proteins, high-resolution cryoEM analyses of the full pore have identified regulatory roles for auxiliary domains 15,17,18 that control the transition from stable proteins in our blood to lethal transmembrane pores.…”

Section: Introductionmentioning

confidence: 99%

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Single-molecule kinetics of pore assembly by the membrane attack complex

Parsons

Stanley

Pyne

et al. 2018

Preprint

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The membrane attack complex (MAC) is a hetero-oligomeric protein assembly that kills pathogens by perforating their cell envelopes. The MAC is formed by sequential assembly of soluble complement proteins C5b, C6, C7, C8 and C9, but little is known about the rate-limiting steps in this process. Here, we use rapid atomic force microscopy (AFM) imaging to show that MAC proteins oligomerize within the membrane, unlike structurally homologous bacterial pore-forming toxins. C5b6 interacts with the lipid bilayer prior to recruiting C7 and C8. We discover that incorporation of the first C9 is the kinetic bottleneck of MAC formation, after which rapid C9 oligomerization completes the pore. This defines the kinetic basis for MAC assembly and provides insight into how human cells are protected from bystander damage by the cell surface receptor CD59, which is offered a maximum temporal window to halt the assembly at the point of C9 insertion.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Single-molecule kinetics of pore assembly by the membrane attack complex

Parsons

Stanley

Pyne

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…This process results in cell membrane pore formation. [19][20][21][22] The mechanism of pore formation contrasts with pore formation via proteins such as perforin and the cholesterol dependent cytolysins, where it is believed that pre-pore assembly happens prior to the concurrent release of the transmembrane regions. 22 The activation of complement and the subsequent formation of complement/C5b-9 open channels on cell membranes, usually leading to cell death.…”

Section: Discussionmentioning

confidence: 99%

Membrane attack complex (C5b‐9 complex or Mac), is strongly present in lesional skin from patients with endemic pemphigus foliaceus in El Bagre, Colombia

et al. 2019

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Background El Bagre endemic pemphigus foliaceus (El Bagre‐EPF) is a new variant of endemic pemphigus foliaceus present in the El Bagre area of Colombia, South America. Here, we investigate the presence of complement/C5‐b9 in lesional skin of patients and matched controls from the endemic area. We also aim to compare the patient's autoantibody levels using indirect immunofluorescent titers (IIF) and correlate with the lesional presence of complement/C5b‐9. Methods A case‐control study was carried out by testing for the presence of complement/C5b‐9 in lesional skin in 43 patients affected by El Bagre‐EPF, as well as 43 matched, healthy controls from the endemic area. Skin biopsies were obtained and evaluated via hematoxylin and eosin staining, and immunohistochemistry. Results The presence of complement/C5b‐9 was observed in all cases of the patients affected by El Bagre‐EPF and was not observed in the controls from the endemic area (P < 0.001). The patients' autoantibody titers utilizing IIF for IgG and IgM showed correlation between higher autoantibody titers and stronger intensity of staining with complement/C5‐b9 staining (P < 0.001). Conclusion Patients affected by El Bagre‐EPF have lesional deposition of complement/C5b, which correlates with disease severity and previously established serologies.

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“…As determined by flicker spectroscopy, the interaction of C5b-7 with the membrane lowers the energy required to bend the bilayer. Finally, Dudkina et al [51] and Spicer et al [52] have determined the structure of monomeric murine C9 and of spontaneously self-polymerized poly-C9. Moreover, 3D classification procedures resolved MAC pores with an "open" and a "closed" chasm between the terminal C9 and C6.…”

Section: Structural Insights Into How the Mac Ruptures Lipid Membranesmentioning

confidence: 99%

How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram‐Negative Bacteria

2019

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The human immune system can directly lyse invading micro-organisms and aberrant host cells by generating pores in the cell envelope, called membrane attack complexes (MACs). Recent studies using single-particle cryoelectron microscopy have revealed that the MAC is an asymmetric, flexible pore and have provided a structural basis on how the MAC ruptures single lipid membranes. Despite these insights, it remains unclear how the MAC ruptures the composite cell envelope of Gram-negative bacteria. Recent functional studies on Gram-negative bacteria elucidate that local assembly of MAC pores by surface-bound C5 convertase enzymes is essential to stably insert these pores into the bacterial outer membrane (OM). These convertase-generated MAC pores can subsequently efficiently damage the bacterial inner membrane (IM), which is essential for bacterial killing. This review summarizes these recent insights of MAC assembly and discusses how MAC pores kill Gramnegative bacteria. Furthermore, this review elaborates on how MAC-dependent OM damage could lead to IM destabilization, which is currently not well understood. A better understanding on how MAC pores kill bacteria could facilitate the future development of novel strategies to treat infections with Gram-negative bacteria.

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

Cited by 55 publications

References 50 publications

Single-molecule kinetics of pore assembly by the membrane attack complex

Single-molecule kinetics of pore assembly by the membrane attack complex

Membrane attack complex (C5b‐9 complex or Mac), is strongly present in lesional skin from patients with endemic pemphigus foliaceus in El Bagre, Colombia

How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram‐Negative Bacteria

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