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The MACPF/CDC family of pore-forming toxins.

Rosado CJ, Kondos S, Bull TE, Kuiper MJ, Law RH, Buckle AM, Voskoboinik I, Bird PI, Trapani JA, Whisstock JC, Dunstone MA - Cell. Microbiol. (2008)

Bottom Line: Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane beta-barrel.In contrast, the structure and mechanism of MACPF proteins has remained obscure.Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Monash University, Clayton, Victoria 3800, Australia.

ABSTRACT
Pore-forming toxins (PFTs) are commonly associated with bacterial pathogenesis. In eukaryotes, however, PFTs operate in the immune system or are deployed for attacking prey (e.g. venoms). This review focuses upon two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF). CDCs are produced by Gram-positive bacteria and lyse or permeabilize host cells or intracellular organelles during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles and function in immunity, invasion and development. The structure and molecular mechanism of several CDCs are relatively well characterized. Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane beta-barrel. In contrast, the structure and mechanism of MACPF proteins has remained obscure. Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold. Together with biochemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development.

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Model of the pore form of a MACPF proteins in a lipid bilayer (using the Plu-MACPF structure as a template, PDB ID: 2QP2).
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fig02: Model of the pore form of a MACPF proteins in a lipid bilayer (using the Plu-MACPF structure as a template, PDB ID: 2QP2).

Mentions: In the absence of structural information, and based upon bioinformatic studies, it was originally proposed that C9 and perforin insert into membranes using two predicted amphipathic α-helices that map to the most conserved region of the MACPF domain (residues 292–333 of the human C9 sequence; Peitsch et al., 1990). Therefore, it was postulated that C9 and perforin belonged to the α-PFT class of toxins. Several recently determined structures challenge this hypothesis. The X-ray crystal structure of Plu-MACPF (a MACPF domain containing protein from Photorhabdus luminescens; Rosado et al., 2007; Fig. 1C), the MACPF domain of C8α (Hadders et al., 2007) and the MACPF domain of C8α in complex with C8γ (Slade et al., 2008) reveal that the MACPF domain is homologous to the N-terminal portion (domains I–III) of CDCs (Fig. 1C). In particular, conservation of a complex core fold, including the membrane spanning clusters of helices (TMH1-2 or CH1-2) suggests strongly that MACPF proteins and CDCs form pores using a analogous mechanism (Fig. 2). Interestingly, it appears that highly conserved MACPF signature sequences (Ponting, 1999) map to regions that may be crucial for controlling conformational change and unfurling of the membrane spanning regions for the MACPF subclass of the MACPF/CDC family of proteins.


The MACPF/CDC family of pore-forming toxins.

Rosado CJ, Kondos S, Bull TE, Kuiper MJ, Law RH, Buckle AM, Voskoboinik I, Bird PI, Trapani JA, Whisstock JC, Dunstone MA - Cell. Microbiol. (2008)

Model of the pore form of a MACPF proteins in a lipid bilayer (using the Plu-MACPF structure as a template, PDB ID: 2QP2).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654483&req=5

fig02: Model of the pore form of a MACPF proteins in a lipid bilayer (using the Plu-MACPF structure as a template, PDB ID: 2QP2).
Mentions: In the absence of structural information, and based upon bioinformatic studies, it was originally proposed that C9 and perforin insert into membranes using two predicted amphipathic α-helices that map to the most conserved region of the MACPF domain (residues 292–333 of the human C9 sequence; Peitsch et al., 1990). Therefore, it was postulated that C9 and perforin belonged to the α-PFT class of toxins. Several recently determined structures challenge this hypothesis. The X-ray crystal structure of Plu-MACPF (a MACPF domain containing protein from Photorhabdus luminescens; Rosado et al., 2007; Fig. 1C), the MACPF domain of C8α (Hadders et al., 2007) and the MACPF domain of C8α in complex with C8γ (Slade et al., 2008) reveal that the MACPF domain is homologous to the N-terminal portion (domains I–III) of CDCs (Fig. 1C). In particular, conservation of a complex core fold, including the membrane spanning clusters of helices (TMH1-2 or CH1-2) suggests strongly that MACPF proteins and CDCs form pores using a analogous mechanism (Fig. 2). Interestingly, it appears that highly conserved MACPF signature sequences (Ponting, 1999) map to regions that may be crucial for controlling conformational change and unfurling of the membrane spanning regions for the MACPF subclass of the MACPF/CDC family of proteins.

Bottom Line: Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane beta-barrel.In contrast, the structure and mechanism of MACPF proteins has remained obscure.Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Monash University, Clayton, Victoria 3800, Australia.

ABSTRACT
Pore-forming toxins (PFTs) are commonly associated with bacterial pathogenesis. In eukaryotes, however, PFTs operate in the immune system or are deployed for attacking prey (e.g. venoms). This review focuses upon two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF). CDCs are produced by Gram-positive bacteria and lyse or permeabilize host cells or intracellular organelles during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles and function in immunity, invasion and development. The structure and molecular mechanism of several CDCs are relatively well characterized. Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane beta-barrel. In contrast, the structure and mechanism of MACPF proteins has remained obscure. Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold. Together with biochemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development.

Show MeSH
Related in: MedlinePlus