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Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin

Nature Structural Biology volume 9, pages 823–827 (2002)Cite this article

Abstract

Perfringolysin O (PFO), a cytolytic toxin secreted by pathogenic Clostridium perfringens, forms large pores in cholesterol-containing membranes. Domain 4 (D4) of the protein interacts first with the membrane and is responsible for cholesterol recognition. By using several independent fluorescence techniques, we have determined the topography of D4 in the membrane-inserted oligomeric form of the toxin. Only the short hydrophobic loops at the tip of the D4 β-sandwich are exposed to the bilayer interior, whereas the remainder of D4 projects from the membrane surface and is surrounded by water, making little or no contact with adjacent protein monomers in the oligomer. Thus, a limited interaction of D4 with the bilayer core seems to be sufficient to accomplish cholesterol recognition and initial binding of PFO to the membrane. Furthermore, D4 serves as the fulcrum around which extensive structural changes occur during the formation and insertion of the large transmembrane β-barrel into the bilayer.

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Figure 1: PFO structure.
Figure 2: D4 probe environments.
Figure 3: D4 topography in the membrane-inserted oligomer.

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Acknowledgements

This work was supported by NIH and by the Robert A. Welch Foundation.

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Texas A&M University, College Station, 77843, Texas, USA

    Rajesh Ramachandran & Arthur E. Johnson

  2. Department of Medical Biochemistry and Genetics, Texas A&M University System Health Science Center, College Station, 77843-1114, Texas, USA

    Alejandro P. Heuck & Arthur E. Johnson

  3. Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, 73104, Oklahoma, USA

    Rodney K. Tweten

  4. Department of Chemistry, Texas A&M University, College Station, 77843, Texas, USA

    Arthur E. Johnson

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  1. Rajesh Ramachandran
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  2. Alejandro P. Heuck
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Correspondence to Arthur E. Johnson.

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Ramachandran, R., Heuck, A., Tweten, R. et al. Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin. Nat Struct Mol Biol 9, 823–827 (2002). https://doi.org/10.1038/nsb855

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