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J. Biol. Chem., Vol. 283, Issue 11, 6668-6676, March 14, 2008

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Direct Hemin Transfer from IsdA to IsdC in the Iron-regulated Surface Determinant (Isd) Heme Acquisition System of Staphylococcus aureus^*

Mengyao Liu, Wesley N. Tanaka, Hui Zhu, Gang Xie, David M. Dooley, and Benfang Lei¹

From the Departments of Veterinary Molecular Biology and Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59718

The iron-regulated surface determinants (Isd) of Staphylococcus aureus, including surface proteins IsdA, IsdB, IsdC, and IsdH and ATP-binding cassette transporter IsdDEF, constitute the machinery for acquiring heme as a preferred iron source. Here we report hemin transfer from hemin-containing IsdA (holo-IsdA) to hemin-free IsdC (apo-IsdC). The reaction has an equilibrium constant of 10 ± 5 at 22 °C in favor of holo-IsdC formation. During the reaction, holo-IsdA binds to apo-IsdC and then transfers the cofactor to apo-IsdC with a rate constant of 54.3 ± 1.8 s^–1 at 25 °C. The transfer rate is >70,000 times greater than the rate of simple hemin dissociation from holo-IsdA into solvent (k_transfer = 54.3 s^–1 versus k_–hemin = 0.00076 s^–1). The standard free energy change, G⁰, is –27 kJ/mol for the formation of the holo-IsdA-apo-IsdC complex. IsdC has a higher affinity for hemin than IsdA. These results indicate that the IsdA-to-IsdC hemin transfer is through the activated holo-IsdA-apo-IsdC complex and is driven by the higher affinity of apo-IsdC for the cofactor. These findings demonstrate for the first time in the Isd system that heme transfer is rapid, direct, and affinity-driven from IsdA to IsdC. These results also provide the first example of heme transfer from one surface protein to another surface protein in Gram-positive bacteria and, perhaps most importantly, indicate that the mechanism of activated heme transfer, which we previously demonstrated between the streptococcal proteins Shp and HtsA, may apply in general to all bacterial heme transport systems.

Received for publication, October 9, 2007 , and in revised form, January 2, 2008.

^* This work was supported in part by National Center for Research Resources Grant P20 RR-020185 (to B. L.), National Institutes of Health Grant GM27659 (to D. M. D.), United States Department of Agriculture Grant NRI/CSREES 2007-35204-18306, Formula Funds and the Montana State University Agricultural Experimental Station, and National Science Foundation Research Experience Undergraduates Program Grant DBI-0453021 (to A. Metz). 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: Dept. of Veterinary Molecular Biology, Montana State University, P. O. Box 173610, Bozeman, MT 59717. Tel.: 406-994-6389; Fax: 406-994-4303; E-mail: blei{at}montana.edu.

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