Crystal Structure of the Heme-IsdC Complex, the Central Conduit of the Isd Iron/Heme Uptake System in Staphylococcus aureus

Sharp, Katherine H.; Schneider, Sabine; Cockayne, Alan; Paoli, Max

doi:10.1074/jbc.m700234200

Cited by 107 publications

(177 citation statements)

References 41 publications

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“…1B). These spectral characteristics are consistent with the pentacoordination of the heme iron in the crystal structure of IsdC (20).…”

Section: Resultssupporting

confidence: 70%

“…The S. pyogenes system has a homologue in S. equi (9), whereas the homologue of the S. aureus system is present in B. anthracis (12). These surface proteins, but not Shp, contain the NEAr transporter (NEAT) domains (17), although the structure of the Shp heme-binding domain (18) is similar to that of the NEAT domains of IsdA (19) and IsdC (20).…”

mentioning

confidence: 97%

“…IsdA and the B. anthracis homologue of IsdC are also important for hemin uptake (12,19). IsdB, IsdA, and IsdC bind heme (11,19,20,23,24), and structural studies show that IsdA and IsdC bind hemin in a pentacoordinate complex with a tyrosine residue as the only axial ligand (19,20), in contrast to the hexacoordination of the heme iron in Shp and HtsA (14,15). It has been proposed that IsdH and IsdB capture haptoglobin-hemoglobin and hemoglobin, respectively, and heme is transferred from bound hemoglobin to IsdA, then IsdC, and finally to ABC transporters IsdDEF and/or HtsABC (25,26).…”

mentioning

confidence: 99%

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Direct Hemin Transfer from IsdA to IsdC in the Iron-regulated Surface Determinant (Isd) Heme Acquisition System of Staphylococcus aureus

Liu

Tanaka

Zhu

et al. 2008

Journal of Biological Chemistry

108

147

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The iron-regulated surface determinants (Isd) of Staphylococcus aureus, including surface proteins IsdA, IsdB, IsdC, and IsdH and ATP-binding cassette transporter IsdDEF, constitute the machinery for acquiring heme as a preferred iron source. Here we report hemin transfer from hemin-containing IsdA (holo-IsdA) to hemin-free IsdC (apo-IsdC). The reaction has an equilibrium constant of 10 ؎ 5 at 22°C in favor of holo-IsdC formation. During the reaction, holo-IsdA binds to apo-IsdC and then transfers the cofactor to apo-IsdC with a rate constant of 54.3 ؎ 1.8 s ؊1 at 25°C. The transfer rate is >70,000 times greater than the rate of simple hemin dissociation from holoIsdA into solvent (k transfer ‫؍‬ 54.3 s ؊1 versus k ؊hemin ‫؍‬ 0.00076 s ؊1 ). The standard free energy change, ⌬G 0 , is ؊27 kJ/mol for the formation of the holo-IsdA-apo-IsdC complex. IsdC has a higher affinity for hemin than IsdA. These results indicate that the IsdA-to-IsdC hemin transfer is through the activated holoIsdA-apo-IsdC complex and is driven by the higher affinity of apo-IsdC for the cofactor. These findings demonstrate for the first time in the Isd system that heme transfer is rapid, direct, and affinity-driven from IsdA to IsdC. These results also provide the first example of heme transfer from one surface protein to another surface protein in Gram-positive bacteria and, perhaps most importantly, indicate that the mechanism of activated heme transfer, which we previously demonstrated between the streptococcal proteins Shp and HtsA, may apply in general to all bacterial heme transport systems.

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“…1B). These spectral characteristics are consistent with the pentacoordination of the heme iron in the crystal structure of IsdC (20).…”

Section: Resultssupporting

confidence: 70%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Direct Hemin Transfer from IsdA to IsdC in the Iron-regulated Surface Determinant (Isd) Heme Acquisition System of Staphylococcus aureus

Liu

Tanaka

Zhu

et al. 2008

Journal of Biological Chemistry

108

147

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show abstract

“…It is not clear if PhuR represents a higher affinity receptor, however, it is interesting that the His-Tyr heme ligation found in PhuR is an emerging motif in the high affinity lipid anchored heme receptors of Gram-positive organisms (27)(28)(29), the soluble periplasmic heme-binding proteins (30,31), and the HasA-secreted hemophores of Gram-negative pathogens (18,19,32). We propose P. aeruginosa has exploited the higher affinity His-Tyr ligation for the soluble extracellular HasA "heme sensor" and the high capacity PhuR receptor to rapidly respond and transport heme across a wide range of physiological concentrations within the host.…”

Section: Discussionmentioning

confidence: 99%

“…Recent spectroscopic characterization of the PhuR receptor by our laboratory revealed heme is coordinated through His-124 of the N-terminal plug and Tyr-519 of the FRAP/PNPL loop. 3 Interestingly, His-Tyr heme coordination is a common motif in the lipid anchored surface exposed heme receptors of Gram-positive pathogens such as Staphylococcus aureus (27)(28)(29), the soluble periplasmic heme-binding proteins (30,31) and the HasA secreted hemophores of Gram-negative pathogens (18,19,32).…”

mentioning

confidence: 99%

Differential Contributions of the Outer Membrane Receptors PhuR and HasR to Heme Acquisition in Pseudomonas aeruginosa

Smith

Wilks

2015

Journal of Biological Chemistry

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Background: Pseudomonas aeruginosa utilizes extracellular heme as a source of iron on infection of the host. Results: Both PhuR and HasR are required for efficient utilization of heme by P. aeruginosa. Conclusion: Non-redundant outer membrane receptors allow for heme acquisition across a range of physiological conditions. Significance: PhuR and HasR have complimentary roles in heme acquisition and utilization.

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Mycobacterium tuberculosis low molecular weight T‐cell antigen Mtb8.4 has heme‐binding and fiber‐forming properties

et al. 2022

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Mtb8.4, a secretory T‐cell antigen of Mycobacterium tuberculosis, is important for providing an antigen‐specific immune response. In this study, we showed Mtb8.4 to have both heme‐binding and fibril‐forming properties, using experimental and in silico methods. High absorbance at 410 nm and interaction with hemin‐agarose demonstrated its heme‐binding nature. Titration of Mtb8.4 with heme resulted in 1 : 1 stoichiometry. The heme‐binding pocket in Mtb8.4 was identified by molecular modeling, and binding residues were predicted using molecular docking. The molecular dynamics simulations of apo‐ and heme‐bound Mtb8.4 confirmed that the heme group forms a stable complex. Transmission electron microscopy analyses and dye‐binding assays showed that Mtb8.4 forms fibers. Computational studies predicted that the C‐terminal sequence (93AAQYIGLVESV103) is important for forming fibers. In silico analyses further anticipated the probable epitope (82AMAAQLQAV90) of Mtb8.4. The fiber‐forming properties of Mtb8.4 could be advantageous from a vaccine perspective for aggregate/fibril‐based vaccine delivery or it might influence the epitope presentation of Mtb8.4.

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Crystal Structure of the Heme-IsdC Complex, the Central Conduit of the Isd Iron/Heme Uptake System in Staphylococcus aureus

Cited by 107 publications

References 41 publications

Direct Hemin Transfer from IsdA to IsdC in the Iron-regulated Surface Determinant (Isd) Heme Acquisition System of Staphylococcus aureus

Direct Hemin Transfer from IsdA to IsdC in the Iron-regulated Surface Determinant (Isd) Heme Acquisition System of Staphylococcus aureus

Differential Contributions of the Outer Membrane Receptors PhuR and HasR to Heme Acquisition in Pseudomonas aeruginosa

Mycobacterium tuberculosis low molecular weight T‐cell antigen Mtb8.4 has heme‐binding and fiber‐forming properties

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