The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism

Mueller, M. and Grauschopf, U. and Maier, T. and Glockshuber, R. and Ban, N.. (2009) The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism. Nature, 459 (7247). pp. 726-730.

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Official URL: http://edoc.unibas.ch/45841/

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Pore-forming toxins (PFTs) are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore(1). They exhibit their toxic effect either by destruction of the membrane permeability barrier or by delivery of toxic components through the pores. Among the group of bacterial PFTs are some of the most dangerous toxins, such as diphtheria and anthrax toxin. Examples of eukaryotic PFTs are perforin and the membrane-attack complex, proteins of the immune system(2). PFTs can be subdivided into two classes, alpha-PFTs and beta-PFTs, depending on the suspected mode of membrane integration, either by alpha-helical or beta-sheet elements(3). The only high-resolution structure of a transmembrane PFT pore is available for a beta-PFT-alpha-haemolysin from Staphylococcus aureus 4. Cytolysin A (ClyA, also known as HlyE), an alpha-PFT, is a cytolytic alpha-helical toxin responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains(5-8). ClyA is cytotoxic towards cultured mammalian cells, induces apoptosis of macrophages and promotes tissue pervasion(9-11). Electron microscopic reconstructions demonstrated that the soluble monomer of ClyA(12) must undergo large conformational changes to form the transmembrane pore(13,14). Here we report the 3.3 angstrom crystal structure of the 400 kDa dodecameric transmembrane pore formed by ClyA. The tertiary structure of ClyA protomers in the pore is substantially different from that in the soluble monomer. The conversion involves more than half of all residues. It results in large rearrangements, up to 140 angstrom, of parts of the monomer, reorganization of the hydrophobic core, and transitions of beta-sheets and loop regions to alpha-helices. The large extent of interdependent conformational changes indicates a sequential mechanism for membrane insertion and pore formation.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
UniBasel Contributors:Maier, Timm
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:29 Nov 2017 08:57
Deposited On:29 Nov 2017 08:57

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