title: Staphylococcus aureus uses a novel multidomain receptor to break apart human hemoglobin and steal its heme.
abstract: Staphylococcus aureus is a leading cause of life-threatening infections in the United States. It requires iron to grow, which must be actively procured from its host to successfully mount an infection. Heme-iron within hemoglobin (Hb) is the most abundant source of iron in the human body and is captured by S. aureus using two closely related receptors, IsdH and IsdB. Here we demonstrate that each receptor captures heme using two conserved near iron transporter (NEAT) domains that function synergistically. NMR studies of the 39-kDa conserved unit from IsdH (IsdH(N2N3), Ala(326)-Asp(660)) reveals that it adopts an elongated dumbbell-shaped structure in which its NEAT domains are properly positioned by a helical linker domain, whose three-dimensional structure is determined here in detail. Electrospray ionization mass spectrometry and heme transfer measurements indicate that IsdH(N2N3) extracts heme from Hb via an ordered process in which the receptor promotes heme release by inducing steric strain that dissociates the Hb tetramer. Other clinically significant Gram-positive pathogens capture Hb using receptors that contain multiple NEAT domains, suggesting that they use a conserved mechanism.
authors.affiliation: Department of Chemistry and Biochemistry and the UCLA-Department of Energy Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spirig
authors.forename: G Reza
authors.initials: GR
authors.lastname: Malmirchegini
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Scott A
authors.initials: SA
authors.lastname: Robson
authors.forename: Megan
authors.initials: M
authors.lastname: Sjodt
authors.forename: Mengyao
authors.initials: M
authors.lastname: Liu
authors.forename: Kaavya
authors.initials: K
authors.lastname: Krishna Kumar
authors.forename: Claire F
authors.initials: CF
authors.lastname: Dickson
authors.forename: David A
authors.initials: DA
authors.lastname: Gell
authors.forename: Benfang
authors.initials: B
authors.lastname: Lei
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Loo
authors.forename: Robert T
authors.initials: RT
authors.lastname: Clubb
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D003001:Cloning, Molecular; D006418:Heme / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D027682:Cation Transport Proteins; D006454:Hemoglobins; C510010:IsdB protein, Staphylococcus aureus; C512792:IsdH protein, Staphylococcus aureus; D011956:Receptors, Cell Surface; D006418:Heme