title: Structural basis for hemoglobin capture by Staphylococcus aureus cell-surface protein, IsdH.
abstract: Pathogens must steal iron from their hosts to establish infection. In mammals, hemoglobin (Hb) represents the largest reservoir of iron, and pathogens express Hb-binding proteins to access this source. Here, we show how one of the commonest and most significant human pathogens, Staphylococcus aureus, captures Hb as the first step of an iron-scavenging pathway. The x-ray crystal structure of Hb bound to a domain from the Isd (iron-regulated surface determinant) protein, IsdH, is the first structure of a Hb capture complex to be determined. Surface mutations in Hb that reduce binding to the Hb-receptor limit the capacity of S. aureus to utilize Hb as an iron source, suggesting that Hb sequence is a factor in host susceptibility to infection. The demonstration that pathogens make highly specific recognition complexes with Hb raises the possibility of developing inhibitors of Hb binding as antibacterial agents.
authors.affiliation: School of Molecular Bioscience, University of Sydney, New South Wales 2006, Australia.
authors.forename: Kaavya
authors.initials: K
authors.lastname: Krishna Kumar
authors.affiliation: School of Molecular Bioscience, University of Sydney, New South Wales 2006, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacques
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232.
authors.forename: Gleb
authors.initials: G
authors.lastname: Pishchany
authors.affiliation: Australian Synchrotron, Clayton, Victoria 3168, Australia.
authors.forename: Tom
authors.initials: T
authors.lastname: Caradoc-Davies
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spirig
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095.
authors.forename: G Reza
authors.initials: GR
authors.lastname: Malmirchegini
authors.affiliation: School of Molecular Bioscience, University of Sydney, New South Wales 2006, Australia.
authors.forename: David B
authors.initials: DB
authors.lastname: Langley
authors.affiliation: Menzies Research Institute, University of Tasmania, Tasmania 7000, Australia.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Dickson
authors.affiliation: School of Molecular Bioscience, University of 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: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.affiliation: School of Molecular Bioscience, University of Sydney, New South Wales 2006, Australia.
authors.forename: J Mitchell
authors.initials: JM
authors.lastname: Guss
authors.affiliation: Menzies Research Institute, University of Tasmania, 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* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D006454:Hemoglobins / Q000737:chemistry*; D006801:Humans; D007501:Iron / Q000737:chemistry; D008024:Ligands; D008027:Light; D008968:Molecular Conformation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013203:Staphylococcal Infections / Q000378:metabolism / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D006454:Hemoglobins; C512792:IsdH protein, Staphylococcus aureus; D008024:Ligands; D011956:Receptors, Cell Surface; D007501:Iron