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J. Biol. Chem., Vol. 282, Issue 39, 28815-28822, September 28, 2007

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Heme Coordination by Staphylococcus aureus IsdE^*

Jason C. Grigg¹, Christie L. Vermeiren, David E. Heinrichs, and Michael E. P. Murphy²

From the Department of Microbiology and Immunology, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3 and the Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6A 5C1

Staphylococcus aureus is a Gram-positive bacterial pathogen and a leading cause of hospital acquired infections. Because the free iron concentration in the human body is too low to support growth, S. aureus must acquire iron from host sources. Heme iron is the most prevalent iron reservoir in the human body and a predominant source of iron for S. aureus. The iron-regulated surface determinant (Isd) system removes heme from host heme proteins and transfers it to IsdE, the cognate substrate-binding lipoprotein of an ATP-binding cassette transporter, for import and subsequent degradation. Herein, we report the crystal structure of the soluble portion of the IsdE lipoprotein in complex with heme. The structure reveals a bi-lobed topology formed by an N- and C-terminal domain bridged by a single -helix. The structure places IsdE as a member of the helical backbone metal receptor superfamily. A six-coordinate heme molecule is bound in the groove established at the domain interface, and the heme iron is coordinated in a novel fashion for heme transporters by Met⁷⁸ and His²²⁹. Both heme propionate groups are secured by H-bonds to IsdE main chain and side chain groups. Of these residues, His²²⁹ is essential for IsdE-mediated heme uptake by S. aureus when growth on heme as a sole iron source is measured. Multiple sequence alignments of homologues from several other Gram-positive bacteria, including the human pathogens pyogenes, Bacillus anthracis, and Listeria monocytogenes, suggest that these other systems function equivalently to S. aureus IsdE with respect to heme binding and transport.

Received for publication, June 5, 2007 , and in revised form, July 7, 2007.

The atomic coordinates and structure factors (code 2Q8Q, 2Q8P) 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 Canadian Institutes of Health Research operating Grants MOP-49597 and MOP-38002 (to M. E. P. M. and D. E. H., respectively). 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 Figs. 1-5.

¹ Recipient of a Natural Sciences and Engineering Research Council Post Graduate Scholarship and a Michael Smith Foundation for Health Research Junior Graduate Trainee award.

² To whom correspondence should be addressed: Tel.: 604-822-0254; Fax: 604-822-6041; E-mail: Michael.Murphy{at}ubc.ca.

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