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J. Biol. Chem., Vol. 281, Issue 35, 25541-25550, September 1, 2006

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The Heme Transfer from the Soluble HasA Hemophore to Its Membrane-bound Receptor HasR Is Driven by Protein-Protein Interaction from a High to a Lower Affinity Binding Site^*

Nadia Izadi-Pruneyre, Frédéric Huché¹, Gudrun S. Lukat-Rodgers^¶, Anne Lecroisey, Robert Gilli^||, Kenton R. Rodgers^¶, Cécile Wandersman, and Philippe Delepelaire²

From the Unité des Membranes Bactériennes, CNRS URA 2172 Département de Microbiologie and Unité de Résonance Magnétique Nucléaire des Biomolécules CNRS URA 2185 Département de Biologie Structurale et de la Chimie, Institut Pasteur, 75724 Paris Cedex 15 France, ^||CNRS FRE 2737, Université de la Méditerranée (Aix-Marseille II), Faculté de Pharmacie 13385 Marseille Cedex 05 France, and ^¶Department of Chemistry, Biochemistry, and Molecular Biology, North Dakota State University, Fargo, North Dakota 58105-5516

HasA is an extracellular heme binding protein, and HasR is an outer membrane receptor protein from Serratia marcescens. They are the initial partners of a heme internalization system allowing S. marcescens to scavenge heme at very low concentrations due to the very high affinity of HasA for heme (K_a = 5,3 x 10¹⁰ M^-1). Heme is then transferred to HasR, which has a lower affinity for heme. The mechanism of the heme transfer between HasA and HasR is largely unknown. HasR has been overexpressed and purified in holo and apo forms. It binds one heme molecule with a K_a of 5 x 10⁶ M^-1 and shows the characteristic absorbance spectrum of a low spin heme iron. Both holoHasA and apoHasA bind tightly to apoHasR in a 1:1 stoichiometry. In this study we show that heme transfer occurs in vitro in the purified HasA·HasR complex, demonstrating that heme transfer is energy- and TonB complex-independent and driven by a protein-protein interaction. We also show that heme binding to HasR involves two conserved histidine residues.

Received for publication, April 18, 2006 , and in revised form, June 9, 2006.

^* This work was supported in part by NCRR Grant P20 RR15556 and United States Department of Agriculture Grant ND05299 (to K. R. R.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ Supported by a fellowship from the Fondation pour la Recherche Médicale.

² To whom correspondence should be addressed: Unité des Membranes Bactériennes, Département de Microbiologie, Institut Pasteur, 25-28, rue du Dr. Roux, 75724 Paris Cedex 15 France. Tel.: 33-1-40-61-32-76; Fax: 33-1-45-68-87-90; E-mail: pdelep{at}pasteur.fr.

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