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Protein Science (2004), 13:1503-1511. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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High resolution crystallographic studies of {alpha}-hemolysin–phospholipid complexes define heptamer–lipid head group interactions: Implication for understanding protein–lipid interactions

Stefania Galdiero1,2 and Eric Gouaux1

1 Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA
2 Dipartimento di Chimica Biologica & Istituto di Biostrutture e Bioimmagini-CNR, University of Naples "Federico II," 80134, Naples, Italy

(RECEIVED December 10, 2003; FINAL REVISION February 25, 2004; ACCEPTED February 25, 2004)



Abstract

The {alpha}-hemolysin is an archetypal pore-forming protein that is secreted from Staphylococcus aureus as a water-soluble monomer. When the monomer binds to the membrane of a susceptible cell, the membrane-bound molecules assemble into the lytic heptamer. Although a bilayer or a bilayer-like environment are essential to toxin assembly, there is no high resolution information on toxin–phospholipid complexes. We have determined the structures of detergent-solubilized {alpha}-hemolysin heptamer bound to glycerophospho-choline or dipropanoyl glycerophosphocholine at 1.75–1.80 Å resolution and 110 K. The phosphocholine head group binds to each subunit in a crevice between the rim and the stem domains. The quaternary ammonium group interacts primarily with aromatic residues, whereas the phosphodiester moiety interacts with a conserved arginine residue. These structures provide a molecular basis for understanding why {alpha}-hemolysin preferentially assembles on membranes comprised of phosphocholine lipids.

Keywords: integral membrane protein; pore-forming toxin; protein–membrane interactions

Abbreviations: {alpha}HL, {alpha}-hemolysin • {alpha}7, {alpha}HL heptamer • GPC, glycero-phosphocholine • DiC3PC, dipropanoyl glycerophosphocholine • rms, root- mean-square

Reprint requests to: Stefania Galdiero, Dipartimento di Chimica Biologica & Istituto di Biostrutture e Bioimmagini-CNR, University of Naples "Federico II," Via Mezzocannone 6, 80134, Naples, Italy; e-mail: galdiero{at}chemistry.unina.it; fax: +39-0815514305.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03561104.


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