Proteins of the Membrane Attack Complex

Plumb, Mnason E.; Sodetz, James M.

doi:10.1201/b14212-7

Cited by 31 publications

(35 citation statements)

References 141 publications

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“…CD59 protects host cells from complement-mediated lysis during times of bacterial infection when complement is activated. It does so by binding to complement proteins C8α and C9, which are two proteins of the complement system that are necessary for the formation of the complement membrane attack complex (MAC) pore (reviewed in [83]). CD59 is homologously restricted [82]: i.e., it only functions to inhibit the host’s complement and not that of other species.…”

Section: Membrane Recognitionmentioning

confidence: 99%

“…The pore forming complement membrane attack complex (MAC) and perforin define the MACPF protein family (reviewed in [83, 116]), but there are many members that are widespread among both eukaryotes and prokaryotes [117]. The terminal pathway of complement, the MAC, is assembled from C5b, C6, C7, C8 and C9 proteins.…”

Section: The Membrane Attack Complex/perforin Family Proteinsmentioning

confidence: 99%

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Membrane assembly of the cholesterol-dependent cytolysin pore complex

Hotze

Tweten

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

158

180

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The cholesterol-dependent cytolysins (CDCs) are a large family of pore-forming toxins that are produced, secreted and contribute to the pathogenesis of many species of Gram-positive bacteria. The assembly of the CDC pore-forming complex has been under intense study for the past 20 years. These studies have revealed a molecular mechanism of pore formation that exhibits many novel features. The CDCs form large β-barrel pore complexes that are assembled from 35-40 soluble CDC monomers. Pore formation is dependent on the presence of membrane cholesterol, which functions as the receptor for most CDCs. Cholesterol binding initiates significant secondary and tertiary structural changes in the monomers, which lead to the assembly of a large membrane embedded β-barrel pore complex. This review will focus on the molecular mechanism of assembly of the CDC membrane pore complex and how these studies have led to insights into the mechanism of pore formation for other pore-forming proteins.

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Section: Membrane Recognitionmentioning

confidence: 99%

Section: The Membrane Attack Complex/perforin Family Proteinsmentioning

confidence: 99%

Membrane assembly of the cholesterol-dependent cytolysin pore complex

Hotze

Tweten

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

158

180

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“…C6 is a modular protein and shares structural similarity with the other terminal complement components, C7, C8, and C9, all of which participate in the assembly of the membrane attack complex (MAC) [3]. Formation of the MAC is triggered by cleavage of C5 by a C5 convertase, which is followed by sequential interaction of C5b with C6, C7, C8, and C9.…”

Section: Introductionmentioning

confidence: 99%

High prevalence of complement component C6 deficiency among African-Americans in the South-eastern USA

Zhu

Atkinson

Hovanky

et al. 2000

Clinical and Experimental Immunology

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SUMMARYComplement component C6 is a part of the membrane attack complex that forms a pore-like structure in cell membranes following complement activation. De®ciency of terminal complement components including C6 predisposes individuals to infection with Neisseriae. Using polymerase chain reaction/ single-strand conformation polymorphism analysis followed by DNA sequencing, we screened genomic DNA from 200 randomly chosen blacks and an equal number from whites for three loss-of-function C6 mutations. Ten blacks and two whites were found to be heterozygous for one of the mutations. Two of the mutations, 1195delC and 1936delG, were found exclusively in black individuals. A third previously undescribed mutation, 878delA, was found at equal frequency among the two groups. The difference between the two groups was signi®cant (P 0´027), indicating that C6 de®ciency due to these three mutations is more common among blacks than whites in the local area, principally Jefferson County, Alabama. In addition, three previously undescribed point mutations, two of which result in amino acid substitutions, were identi®ed within exon 6. A review of the county health department records over the past 6 years revealed a higher incidence of meningococcal meningitis in blacks due to serogroups Y and W-135 which paralleled the difference in the estimated prevalence of C6 de®ciency. Among black residents of the county (n 235 598) there were 15 cases of meningitis due to these two serogroups, compared with two cases in the white population (n 422 604) (P 0´002). We conclude that C6 de®ciency is more common among blacks than whites in the south-eastern United States, with a frequency approaching 1 in 1600 black individuals.

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“…C6, C7, the C8␣ and C8␤ subunits, and C9 are homologous and together comprise the "MAC family" of proteins (4,5). Until now, structures have not been determined for any of these proteins.…”

mentioning

confidence: 99%

Structure of Human C8 Protein Provides Mechanistic Insight into Membrane Pore Formation by Complement

Lovelace

Cooper

Sodetz

et al. 2011

Journal of Biological Chemistry

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C8 is one of five complement proteins that assemble on bacterial membranes to form the lethal pore-like "membrane attack complex" (MAC) of complement. The MAC consists of one C5b, C6, C7, and C8 and 12-18 molecules of C9. C8 is composed of three genetically distinct subunits, C8␣, C8␤, and C8␥. The C6, C7, C8␣, C8␤, and C9 proteins are homologous and together comprise the MAC family of proteins. All contain N-and C-terminal modules and a central 40-kDa membrane attack complex perforin (MACPF) domain that has a key role in forming the MAC pore. Here, we report the 2.5 Å resolution crystal structure of human C8 purified from blood. This is the first structure of a MAC family member and of a human MACPF-containing protein. The structure shows the modules in C8␣ and C8␤ are located on the periphery of C8 and not likely to interact with the target membrane. The C8␥ subunit, a member of the lipocalin family of proteins that bind and transport small lipophilic molecules, shows no occupancy of its putative ligand-binding site. C8␣ and C8␤ are related by a rotation of ϳ22°with only a small translational component along the rotation axis. Evolutionary arguments suggest the geometry of binding between these two subunits is similar to the arrangement of C9 molecules within the MAC pore. This leads to a model of the MAC that explains how C8-C9 and C9-C9 interactions could facilitate refolding and insertion of putative MACPF transmembrane ␤-hairpins to form a circular pore. Assembly of the "membrane attack complex" (MAC)3 of complement on the surface of Gram-negative bacteria and other pathogenic organisms involves the sequential interaction of complement proteins C5b, C6, C7, C8, and C9 (1-3). Association of the first four components produces a membranebound tetrameric C5b-8 complex, which then initiates the recruitment and sequential binding of 12-18 C9 molecules to form a cylindrical transmembrane pore (supplemental Fig. S1). Pore formation leads to loss of membrane integrity and lysis of the cell under attack.The sequence of interactions leading to MAC formation is well defined; however, the mechanism by which the MAC disrupts membrane organization is poorly understood. C6, C7, the C8␣ and C8␤ subunits, and C9 are homologous and together comprise the "MAC family" of proteins (4, 5). Until now, structures have not been determined for any of these proteins. All contain N-and C-terminal modules and a central 40-kDa "membrane attack complex/perforin" (MACPF) domain. The MACPF domain was named as such because of sequence similarity between the MAC family proteins and perforin. The modules range in number from three to eight; all are small domains of 40 -60 amino acids that contain multiple disulfide bonds (supplemental Fig. S2). One type of module, thrombospondin type 1 (TSP1), contains several mannosylated tryptophans (6).Several hundred MACPF-containing proteins have been identified; however, functions are known for only a few. MACPF proteins exhibit limited sequence similarity, but all contain the MACPF signature motif ((Y/...

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Proteins of the Membrane Attack Complex

Cited by 31 publications

References 141 publications

Membrane assembly of the cholesterol-dependent cytolysin pore complex

Membrane assembly of the cholesterol-dependent cytolysin pore complex

High prevalence of complement component C6 deficiency among African-Americans in the South-eastern USA

Structure of Human C8 Protein Provides Mechanistic Insight into Membrane Pore Formation by Complement

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