Structure of the Hemoglobin-IsdH Complex Reveals the Molecular Basis of Iron Capture by Staphylococcus aureus

Dickson, Claire F.; Kumar, Kaavya Krishna; Jacques, D.A.; Malmirchegini, G. Reza; Spirig, Thomas; Mackay, Joel P.; Clubb, Robert T.; Guss, J. Mitchell; Gell, David A.

doi:10.1074/jbc.m113.545566

Cited by 45 publications

(79 citation statements)

References 73 publications

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“…This is distinct from previously studied Hb-binding NEAT domains from the S. aureus IsdH and IsdB proteins that are incapable of binding hemin (35,48,49). In S. aureus, the IsdB and IsdH proteins use a conserved bidomain unit to extract hemin from Hb in which the NEAT domains function synergistically (12,49,50). Whether the multi-NEAT domain-containing Hbp2 protein uses a similar mechanism remains to be determined.…”

Section: Discussionmentioning

confidence: 86%

Novel Mechanism of Hemin Capture by Hbp2, the Hemoglobin-binding Hemophore from Listeria monocytogenes

Malmirchegini¹,

Sjodt²,

Shnitkind³

et al. 2014

Journal of Biological Chemistry

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Background: Listeria monocytogenes scavenges iron from heme and human hemoglobin using the Hbp1 and Hbp2 proteins. Results: Crystal structures and heme transfer studies of Hbp2 reveal an unusual binding mechanism. Conclusion: Hbp2 is a novel hemoglobin-binding hemophore that rapidly delivers hemin to Hbp1 and other Hbp2 proteins. Significance: These studies provides insight into how L. monocytogenes captures heme iron.

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Section: Discussionmentioning

confidence: 86%

Novel Mechanism of Hemin Capture by Hbp2, the Hemoglobin-binding Hemophore from Listeria monocytogenes

Malmirchegini¹,

Sjodt²,

Shnitkind³

et al. 2014

Journal of Biological Chemistry

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“…The receptor would then undergo a structural transition about the N2-linker interface so as to adopt the more stable conformation observed in the 4.2 Å crystal structure of the IsdH N2N3 :Hb complex (Fig. 8) 29 .…”

Section: Discussionmentioning

confidence: 99%

“…1) 26 . Previously we determined a 4.2 Å structure of the receptor bound to Hb revealing that the receptor adopts an extended structure in which the N2 domain engages the A and E helices of each globin chain enabling the linker domain to properly position the N3 domain near the hemin molecule in the same globin chain 29 . The crystal structure of the complex revealed the overall mode of binding, but it did not define the structure and dynamics of the tri-domain receptor prior to engaging Hb.…”

Section: Discussionmentioning

confidence: 99%

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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

Sjodt

Macdonald

Spirig

et al. 2016

Journal of Molecular Biology

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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 NEAr iron Transporter (NEAT) 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 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 -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.

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“…The sequence encoding IsdH N2N3 (residues 321-655) was cloned in the XhoI and BamHI sites of pET15b (Novagen) in line with the vector encoded His 6 tag and purified over nickel affinity, anion exchange chromatography as previously described (10). IsdH N1N2N3 (residues 82-655) and IsdB N1N2 (residues 120 -459) were expressed and purified according to the same method as used for IsdH N2N3 purification.…”

Section: Methodsmentioning

confidence: 99%

The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

Sæderup

Stødkilde

Graversen

et al. 2016

Journal of Biological Chemistry

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Edited by F. Peter GuengerichHemolysis is a complication in septic infections with Staphylococcus aureus, which utilizes the released Hb as an iron source. S. aureus can acquire heme in vitro from hemoglobin (Hb) by a heme-sequestering mechanism that involves proteins from the S. aureus iron-regulated surface determinant (Isd) system. However, the host has its own mechanism to recapture the free Hb via haptoglobin (Hp) binding and uptake of Hb-Hp by the CD163 receptor in macrophages. It has so far remained unclear how the Isd system competes with this host iron recycling system in situ to obtain the important nutrient.

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Structure of the Hemoglobin-IsdH Complex Reveals the Molecular Basis of Iron Capture by Staphylococcus aureus

Cited by 45 publications

References 73 publications

Novel Mechanism of Hemin Capture by Hbp2, the Hemoglobin-binding Hemophore from Listeria monocytogenes

Novel Mechanism of Hemin Capture by Hbp2, the Hemoglobin-binding Hemophore from Listeria monocytogenes

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

The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

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