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J. Biol. Chem., Vol. 279, Issue 17, 17834-17841, April 23, 2004

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Solution Structure of the Pore-forming Protein of Entamoeba histolytica^*

Oliver Hecht, Nico A. van Nuland, Karin Schleinkofer¶, Andrew J. Dingley||, Heike Bruhn**, Matthias Leippe, and Joachim Grötzinger

From the Biochemisches Institut der Christian-Albrechts-Universität Kiel, Olshausenstr. 40 24118 Kiel, Germany, the Department of NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands, the ^||Department of Biochemistry and Molecular Biology, University College London, Gower Street, London, WC1E 6BT, United Kingdom, ^**Molekulare Parasitologie, Zentrum für Infektionsforschung, Röntgenring 11, 97070 Würzburg, Germany, and Zoologisches Institut der Christian-Albrechts-Universität Kiel, Olshausenstr. 40, 24118 Kiel, Germany

Amoebapore A is a 77-residue protein from the protozoan parasite and human pathogen Entamoeba histolytica. Amoebapores lyse both bacteria and eukaryotic cells by pore formation and play a pivotal role in the destruction of host tissues during amoebiasis, one of the most life-threatening parasitic diseases. Amoebapore A belongs to the superfamily of saposin-like proteins that are characterized by a conserved disulfide bond pattern and a fold consisting of five helices. Membrane-permeabilizing effector molecules of mammalian lymphocytes such as porcine NK-lysin and the human granulysin share these structural attributes. Several mechanisms have been proposed to explain how saposin-like proteins form membrane pores. All mechanisms indicate that the surface charge distribution of these proteins is the basis of their membrane binding capacity and pore formation. Here, we have solved the structure of amoebapore A by NMR spectroscopy. We demonstrate that the specific activation step of amoebapore A depends on a pH-dependent dimerization event and is modulated by a surface-exposed histidine residue. Thus, histidine-mediated dimerization is the molecular switch for pore formation and reveals a novel activation mechanism of pore-forming toxins.

Received for publication, November 30, 2003 , and in revised form, February 9, 2004.

The atomic coordinates and structure factors (code 1OF9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (Grant GR 1623/1-1, LE 1075/2-3, and the SFB 617) and the European UNION (Grant HPRI-CT-2001-00172). 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.

^¶ Present address: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

To whom correspondence should be addressed. Tel.: 49-431-8801686; Fax: 49-431-8805007; E-mail: jgroetzinger{at}biochem.uni-kiel.de.

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