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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

Citation

Sjodt, M and Macdonald, R and Spirig, T and Chan, AH and Dickson, CF and Fabian, M and Olson, JS and Gell, DA and Clubb, RT, 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, (6) pp. 1107-1129. ISSN 0022-2836 (2015) [Refereed Article]

Copyright Statement

Copyright 2015 Published by Elsevier Ltd.

DOI: doi:10.1016/j.jmb.2015.02.008

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, A326D660 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.

Item Details

Item Type:Refereed Article
Keywords:haemoglobin, receptor, iron-regulated surface determinant
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Structural Biology (incl. Macromolecular Modelling)
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Biological Sciences
Author:Dickson, CF (Miss Claire Dickson)
Author:Gell, DA (Dr David Gell)
ID Code:98547
Year Published:2015
Web of Science® Times Cited:5
Deposited By:Medicine (Discipline)
Deposited On:2015-02-19
Last Modified:2017-11-06
Downloads:0

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