title: Structure of the hemoglobin-IsdH complex reveals the molecular basis of iron capture by Staphylococcus aureus.
abstract: Staphylococcus aureus causes life-threatening disease in humans. The S. aureus surface protein iron-regulated surface determinant H (IsdH) binds to mammalian hemoglobin (Hb) and extracts heme as a source of iron, which is an essential nutrient for the bacteria. However, the process of heme transfer from Hb is poorly understood. We have determined the structure of IsdH bound to human Hb by x-ray crystallography at 4.2 Å resolution, revealing the structural basis for heme transfer. One IsdH molecule is bound to each α and β Hb subunit, suggesting that the receptor acquires iron from both chains by a similar mechanism. Remarkably, two near iron transporter (NEAT) domains in IsdH perform very different functions. An N-terminal NEAT domain binds α/β globin through a site distant from the globin heme pocket and, via an intervening structural domain, positions the C-terminal heme-binding NEAT domain perfectly for heme transfer. These data, together with a 2.3 Å resolution crystal structure of the isolated N-terminal domain bound to Hb and small-angle x-ray scattering of free IsdH, reveal how multiple domains of IsdH cooperate to strip heme from Hb. Many bacterial pathogens obtain iron from human hemoglobin using proteins that contain multiple NEAT domains and other domains whose functions are poorly understood. Our results suggest that, rather than acting as isolated units, NEAT domains may be integrated into higher order architectures that employ multiple interaction interfaces to efficiently extract heme from host proteins.
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Dickson
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Kaavya Krishna
authors.initials: KK
authors.lastname: Kumar
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacques
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095.
authors.forename: G Reza
authors.initials: GR
authors.lastname: Malmirchegini
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spirig
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Clubb
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: J Mitchell
authors.initials: JM
authors.lastname: Guss
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania 7000, Australia. Electronic address: david.gell@utas.edu.au.
authors.forename: David A
authors.initials: DA
authors.lastname: Gell
mesh_terms: D000942:Antigens, Bacterial / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006418:Heme / Q000737:chemistry*; D006454:Hemoglobins / Q000737:chemistry*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry*; D013203:Staphylococcal Infections / Q000097:blood / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D006454:Hemoglobins; C512792:IsdH protein, Staphylococcus aureus; D011956:Receptors, Cell Surface; D006418:Heme; D007501:Iron
keywords: Crystallography; Heme; Hemoglobin; Iron-regulated Surface Determinant; NEAT Domain; Protein Domains; Staphylococcus aureus