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J. Biol. Chem., Vol. 282, Issue 31, 22629-22637, August 3, 2007

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Conformational Changes That Effect Oligomerization and Initiate Pore Formation Are Triggered throughout Perfringolysin O upon Binding to Cholesterol^*

Alejandro P. Heuck¹, Christos G. Savva, Andreas Holzenburg^¶||, and Arthur E. Johnson^**||

From the Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Massachusetts 01003, ^¶Microscopy and Imaging Center and Departments of Biology, ^**Chemistry, and ^||Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, and the Department of Molecular and Cellular Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843-1114

Pore formation by the cholesterol-dependent cytolysins (CDCs) requires the presence of cholesterol in the target membrane. Cholesterol was long thought to be the cellular receptor for these toxins, but not all CDCs require cholesterol for binding. Intermedilysin, secreted by Streptococcus intermedius, only binds to membranes containing the human protein CD59 but forms pores only if the membrane contains sufficient cholesterol. In contrast, perfringolysin O (PFO), secreted by Clostridium perfringens, only binds to membranes containing substantial amounts of cholesterol. Given that different steps in the assembly of various CDC pores require cholesterol, here we have analyzed to what extent cholesterol molecules, by themselves, can modulate the conformational changes associated with PFO oligomerization and pore formation. PFO binds to cholesterol when dispersed in aqueous solution, and this binding triggers the distant rearrangement of a -strand that exposes an oligomerization interface. Moreover, upon binding to cholesterol, PFO forms a prepore complex, unfolds two amphipathic transmembrane -hairpins, and positions their nonpolar surfaces so they associate with the hydrophobic cholesterol surface. The interaction of PFO with cholesterol is therefore sufficient to initiate an irreversible sequence of coupled conformational changes that extend throughout the toxin molecule.

Received for publication, April 16, 2007 , and in revised form, June 4, 2007.

^* This work was supported by startup funds provided by the University of Massachusetts, Amherst (to A. P. H.), the Robert A. Welch Foundation Grant BE-0017 (to A. E. J.), and National Institutes of Health Grant AI 37657 (to R. K. T. and A. E. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 710 N. Pleasant St., Lederle GRT 816, Amherst, MA 01003. Tel.: 413-545-2497; Fax: 413-545-3291; E-mail: heuck{at}biochem.umass.edu.

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