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    The PRE-Derived NMR Model of the 38.8-kDa Tri-Domain IsdH Protein from Staphylococcus aureus Suggests That It Adaptively Recognizes Human Hemoglobin

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    Sjodt, Megan; Macdonald, Ramsay; Spirig, Thomas; Chan, Albert H.; Dickson, Claire F.; More... Fabian, Marian; Olson, John S.; Gell, David A.; Clubb, Robert T. Less...
    Date
    2016
    Abstract
    Staphylococcus aureus is a medically important bacterial pathogen that, during infections, acquires iron from human hemoglobin (Hb). It uses two closely related iron-regulated surface determinant (Isd) proteins to capture and extract the oxidized form of heme (hemin) from Hb, IsdH and IsdB. Both receptors rapidly extract hemin using a conserved tri-domain unit consisting of two NEAT (near iron transporter) domains connected by a helical linker domain. To gain insight into the mechanism of extraction, we used NMR to investigate the structure and dynamics of the 38.8-kDa tri-domain IsdH protein (IsdHN2N3, A326–D660 with a Y642A mutation that prevents hemin binding). The structure was modeled using long-range paramagnetic relaxation enhancement (PRE) distance restraints, dihedral angle, small-angle X-ray scattering, residual dipolar coupling and inter-domain NOE nuclear Overhauser effect data. The receptor adopts an extended conformation wherein the linker and N3 domains pack against each other via a hydrophobic interface. In contrast, the N2 domain contacts the linker domain via a hydrophilic interface and, based on NMR relaxation data, undergoes inter-domain motions enabling it to reorient with respect to the body of the protein. Ensemble calculations were used to estimate the range of N2 domain positions compatible with the PRE data. A comparison of the Hb-free and Hb-bound forms reveals that Hb binding alters the positioning of the N2 domain. We propose that binding occurs through a combination of conformational selection and induced-fit mechanisms that may promote hemin release from Hb by altering the position of its F helix.
    Citation
    Sjodt, Megan, Macdonald, Ramsay, Spirig, Thomas, et al.. "The PRE-Derived NMR Model of the 38.8-kDa Tri-Domain IsdH Protein from Staphylococcus aureus Suggests That It Adaptively Recognizes Human Hemoglobin." Journal of Molecular Biology, 428, no. 6 (2016) Elsevier: 1107-1129. https://doi.org/10.1016/j.jmb.2015.02.008.
    Published Version
    https://doi.org/10.1016/j.jmb.2015.02.008
    Keyword
    paramagnetic relaxation enhancement; large protein NMR; iron-regulated surface determinant system; hemoglobin receptor; nuclear magnetic resonance spectroscopy
    Type
    Journal article
    Publisher
    Elsevier
    Citable link to this page
    https://hdl.handle.net/1911/94129
    Rights
    This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier.
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    • Biochemistry and Cell Biology Publications [118]
    • Faculty Publications [4988]

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    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map