The MACPF/CDC family of pore-forming toxins

Rosado, Carlos J.; Kondos, S.C.; Bull, Tara Elaina; Kuiper, Michael J.; Law, Ruby H. P.; Buckle, Ashley M.; Voskoboinik, Ilia; Bird, Phillip I.; Trapani, Joseph A.; Whisstock, James C.; Dunstone, Michelle Anne

doi:10.1111/j.1462-5822.2008.01191.x

Cited by 243 publications

(210 citation statements)

References 76 publications

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“…30 Furthermore, the lack of sequence similarity with other structurally characterized proteins also delayed progress. However, in the year 2007-2008, three independent studies arrived at the same remarkable conclusion: despite sharing minimal amino acid sequence similarity, mammalian and other MACPF proteins are structurally related to bacterial cholesterol-dependent cytolysins (CDCs) and operate by an analogous mechanism.…”

Section: Perforin Biologymentioning

confidence: 99%

“…The predicted similarity between bacterial CDCs and MACPF proteins strongly suggested that PRF pore formation would require major conformational changes, which would only be possible in structurally labile proteins. 30 We therefore hypothesized that cancer-associated mutations, such as A91V, might predominantly result in misfolding rather than loss of function per se. Indeed, by reducing the culture temperature of mutant PRF-expressing cells to 301C to optimize folding, we showed that the activity of most of the mutants could be restored to a significant extent.…”

Section: Perforin Deficiency and Human Cancermentioning

confidence: 99%

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Perforin deficiency and susceptibility to cancer

et al. 2010

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Cytotoxic lymphocytes (CLs) are the killer cells that destroy intracellular pathogen-infected and transformed cells, predominantly through the cytotoxic granule-mediated death pathway. Soluble cytotoxic granule components, including pore-forming perforin and pro-apoptotic serine proteases, granzymes, synergize to induce unscheduled apoptosis of the target cell. A complete loss of CL function results in an aggressive immunoregulatory disorder, familial hemophagocytic lymphohistiocytosis, whereas a partial loss of function seems to be a factor strongly predisposing to hematological malignancies. This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology. Cell Death and Differentiation (2010) 17, 607-615; doi:10.1038/cdd.2009; published online 15 January 2010Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, collectively called cytotoxic lymphocytes (CLs), kill virusinfected and transformed cells through a number of contactdependent mechanisms. 1,2 Engagement of death receptors by membrane-bound members of the TNF superfamily of death ligands is critical for maintaining lymphoid homeostasis in the host. By contrast, studies of gene deficiencies indicate that defects of the granule exocytosis pathway result in a failure to eliminate infected cells or those that pose a risk of subsequent malignancy. Although cytotoxic granules contain diverse toxins that together contribute to apoptosis induction, this review will deal exclusively with the critical role of the pore-forming protein perforin (PRF) as an essential enabler of target-cell apoptosis, and its more recently described role as a potential 'extrinsic' tumor suppressor.Perforin is a 67-kDa pore-forming protein that is stored and released from the secretory granules (SGs) of CLs along with a number of pro-apoptotic serine protease granzymes that display broad substrate specificities. 3 Following exocytic release, PRF and the granzymes are exposed to the neutral pH and calciumrich environment of the immune synapse. 4 After binding calcium through their C2 domains, PRF monomers acquire the ability to bind generic lipids in the target cell membrane, 5 and then coalesce into large transmembrane pores that permit the granzymes to access key death substrates in the cytosol. [6][7][8] Although the diverse apoptotic pathways triggered by granzymes have been extensively studied and are now understood in considerable detail, it is only of late that insights into the molecular and cellular functions of PRF have been even partly addressed.In this review, we will re-examine the pathological consequences of PRF deficiency, both in mice and humans. In doing so, important differences in PRF biology between these species will be described. We will discuss the pathogenic effect of a number of recently described missense mutations of human PRF. In particular, although the complete absence of PRF function typically results in an aggressive, fatal immunoregulatory disorder of ea...

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Section: Perforin Biologymentioning

confidence: 99%

Section: Perforin Deficiency and Human Cancermentioning

confidence: 99%

Perforin deficiency and susceptibility to cancer

et al. 2010

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“…2 This is followed by oligomerization into a large circular pre-pore by lateral interactions of the monomers followed by conformational change of the central MACPF domain, resulting in membrane insertion and formation of a large β-barrel pore of ~100 Å diameter. 18 Functions of these pores include: (1) killing target cells by disrupting their outer membrane as is the case for many bacterial CDCs as well as components of the membrane attack complex (C6-C9); 2 (2) delivering other effector proteins across membranes as in the delivery of granzyme by perforin; 3 or (3) facilitating pathogen traversal of a membrane barrier as in the case of Listeriolysin O mediated release from the phagosome.…”

Section: Functionmentioning

confidence: 99%

“…2 These pre-pores undergo a molecular rearrangement and insert into target membranes to form large pores (~100 Å diameter). 2,3 Exciting work over the past couple of years has provided additional insight into their molecular mechanism of action by revealing that the MACPF fold is shared with that of the cholesterol-dependent cytolysins (CDCs), an extensively studied family of bacterial pore-forming virulence factors. 4,5 Here we present an overview of the Apicomplexan PerforinLike Proteins (ApiPLPs) that have been identified in parasites for which genome sequence is available.…”

Section: Introductionmentioning

confidence: 99%

Apicomplexan perforin-like proteins

Kafsack

Carruthers

2010

Communicative & Integrative Biology

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“…Recently, work in vertebrates has revealed that CDCs and membrane attack complex/perforin superfamily domain-containing proteins share a similar fold, suggesting that vertebrates use a similar mechanism for defense against infection (1,2). A common feature of the CDC family is the requirement of cholesterol in the membrane to form pores (3).…”

mentioning

confidence: 99%

Cellular Functions and X-ray Structure of Anthrolysin O, a Cholesterol-dependent Cytolysin Secreted by Bacillus anthracis

Bourdeau

Malito

Chenal

et al. 2009

Journal of Biological Chemistry

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Anthrolysin O (ALO) is a pore-forming, cholesterol-dependent cytolysin (CDC) secreted by Bacillus anthracis, the etiologic agent for anthrax. Growing evidence suggests the involvement of ALO in anthrax pathogenesis. Here, we show that the apical application of ALO decreases the barrier function of human polarized epithelial cells as well as increases intracellular calcium and the internalization of the tight junction protein occludin. Using pharmacological agents, we also found that barrier function disruption requires increased intracellular calcium and protein degradation. We also report a crystal structure of the soluble state of ALO. Based on our analytical ultracentrifugation and light scattering studies, ALO exists as a monomer. Our ALO structure provides the molecular basis as to how ALO is locked in a monomeric state, in contrast to other CDCs that undergo antiparallel dimerization or higher order oligomerization in solution. ALO has four domains and is globally similar to perfringolysin O (PFO) and intermedilysin (ILY), yet the highly conserved undecapeptide region in domain 4 (D4) adopts a completely different conformation in all three CDCs. Consistent with the differences within D4 and at the D2-D4 interface, we found that ALO D4 plays a key role in affecting the barrier function of C2BBE cells, whereas PFO domain 4 cannot substitute for this role. Novel structural elements and unique cellular functions of ALO revealed by our studies provide new insight into the molecular basis for the diverse nature of the CDC family.Cholesterol-dependent cytolysins (CDCs) 4 are a family of pore-forming toxins from many organisms, including but not limited to the genera Archanobacterium, Bacillus, Clostridium, Listeria, and Streptococcus. Recently, work in vertebrates has revealed that CDCs and membrane attack complex/perforin superfamily domain-containing proteins share a similar fold, suggesting that vertebrates use a similar mechanism for defense against infection (1, 2). A common feature of the CDC family is the requirement of cholesterol in the membrane to form pores (3). In addition to cholesterol, certain members of the family also require a cellular receptor, such as CD59 for the toxin ILY from Streptococcus intermedius (4). The specific mechanism by which CDCs form pores is not completely resolved; however, what is generally known is that ring-shaped oligomerization at the cellular membrane is followed by large conformational changes in each unit of the oligomer, resulting in the insertion of a ␤-barrel into the cellular membrane (5). Pore formation results in a variety of downstream signaling effects, including but not limited to the influx of Ca 2ϩ into the cell (6).A good deal is known about structures of the prepore conformation of CDCs. The crystal structures of prepore PFO, from Clostridium perfringens, and ILY have previously been elucidated (7,8). Each structure shows a characteristic fourdomain architecture, in which domain 4 (D4) is involved in membrane recognition, domain 3 (D3) is involved in ␤...

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The MACPF/CDC family of pore-forming toxins

Cited by 243 publications

References 76 publications

Perforin deficiency and susceptibility to cancer

Perforin deficiency and susceptibility to cancer

Apicomplexan perforin-like proteins

Cellular Functions and X-ray Structure of Anthrolysin O, a Cholesterol-dependent Cytolysin Secreted by Bacillus anthracis

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