CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers

Menny, A.; Serna, Marina; Boyd, Courtney M.; Gardner, Scott; Joseph, Agnel Praveen; Morgan, B. Paul; Topf, Maya; Brooks, Nicholas J.; Bubeck, Doryen

doi:10.1038/s41467-018-07653-5

Cited by 95 publications

(136 citation statements)

References 66 publications

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“…This study was also the first to reveal that the MAC is an asymmetrical pore with a "split-washer" configuration. These protrusions allowed the passage of small molecules (sulforhodamine B) and were consistent with the observations of Menny et al, [29] who used flicker spectroscopy. [29] This structure revealed that the β-hairpins of different MAC components are located at variable heights relative to the membrane.…”

Section: Structural Insights Into How the Mac Ruptures Lipid Membranessupporting

confidence: 89%

“…MAC pores were generated on liposomes in a serum-free manner by mixing preassembled C5b6 together with downstream MAC components C7, C8, and C9. [29] This structure revealed that the β-hairpins of different MAC components are located at variable heights relative to the membrane. The overall pore was shown to be 30.5 nm in its longest dimension, with an outer diameter of 24 nm and an inner diameter of 11 nm.…”

Section: Structural Insights Into How the Mac Ruptures Lipid Membranesmentioning

confidence: 94%

“…[29] This structure revealed that the β-hairpins of different MAC components are located at variable heights relative to the membrane. Interestingly, whereas Serna et al [48] and Menny et al [29] only studied monomeric MAC pores in their analyses, Sharp Figure 1. A structural model and schematic representation of the findings of these papers is depicted in Figure 1B,C.…”

Section: Structural Insights Into How the Mac Ruptures Lipid Membranesmentioning

confidence: 94%

“…[24] Moreover, a high density of C3b on the surface changes the substrate specificity of the convertase from C3 into C5. [29,30] However, it is generally accepted that C5b6 needs to recruit C7 to form a stable C5b7 complex that exposes a lipophilic domain that allows the complex to stably bind to the lipid membranes. Despite the fact that C3b and C5b are highly homologous, C5b is not covalently linked to the target surface.…”

Section: The Assembly Of the Mac Porementioning

confidence: 99%

“…The overall pore was shown to be 30.5 nm in its longest dimension, with an outer diameter of 24 nm and an inner diameter of 11 nm. [29] In the past few years, in situ analysis of MAC pores on liposomes has also become possible by means of cryo-EM tomography (cryo-ET). This study was also the first to reveal that the MAC is an asymmetrical pore with a "split-washer" configuration.…”

Section: Structural Insights Into How the Mac Ruptures Lipid Membranesmentioning

confidence: 99%

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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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Section: Structural Insights Into How the Mac Ruptures Lipid Membranessupporting

confidence: 89%

Section: Structural Insights Into How the Mac Ruptures Lipid Membranesmentioning

confidence: 94%

Section: Structural Insights Into How the Mac Ruptures Lipid Membranesmentioning

confidence: 94%

Section: The Assembly Of the Mac Porementioning

confidence: 99%

Section: Structural Insights Into How the Mac Ruptures Lipid Membranesmentioning

confidence: 99%

See 3 more Smart Citations

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

2019

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Dengue virus and the complement alternative pathway

et al. 2020

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Dengue disease is an inflammatory-driven pathology, and complement overactivation is linked to disease severity and vascular leakage. Additionally, dysregulation of complement alternative pathway (AP) components has been described, such as upregulation of complement factor D and downregulation of complement factor H (FH), which activate and inhibit the AP, respectively. Thus, the pathology of severe dengue could in part result from AP dysfunction, even though complement and AP activation usually provide protection against viral infections. In dengue virus-infected macrophages and endothelial cells (ECs), the site of replication and target for vascular pathology, respectively, the AP is activated. The AP activation, reduced FH and vascular leakage seen in dengue disease in part parallels other complement AP pathologies associated with FH deficiency, such as atypical haemolytic uraemic syndrome (aHUS). aHUS can be therapeutically targeted with inhibitors of complement terminal activity, raising the idea that strategies such as inhibition of complement or delivery of FH or other complement regulatory components to EC may be beneficial to combat the vascular leakage seen in severe dengue.

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Streptococci and the complement system: interplay during infection, inflammation and autoimmunity

et al. 2020

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Streptococci are a broad group of Gram-positive bacteria. This genus includes various human pathogens causing significant morbidity and mortality. Two of the most important human pathogens are Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A streptococcus or GAS). Streptococcal pathogens have evolved to express virulence factors that enable them to evade complement-mediated attack. These include factor Hbinding M (S. pyogenes) and pneumococcal surface protein C (PspC) (S. pneumoniae) proteins. In addition, S. pyogenes and S. pneumoniae express cytolysins (streptolysin and pneumolysin), which are able to destroy host cells. Sometimes, the interplay between streptococci, the complement, and antistreptococcal immunity may lead to an excessive inflammatory response or autoimmune disease. Understanding the fundamental role of the complement system in microbial clearance and the bacterial escape mechanisms is of paramount importance for understanding microbial virulence, in general, and, the conversion of commensals to pathogens, more specifically. Such insights may help to identify novel antibiotic and vaccine targets in bacterial pathogens to counter their growing resistance to commonly used antibiotics.

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CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers

Cited by 95 publications

References 66 publications

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

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

Dengue virus and the complement alternative pathway

Streptococci and the complement system: interplay during infection, inflammation and autoimmunity

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