The Crystal Structure of the Secreted Dimeric Form of the Hemophore HasA Reveals a Domain Swapping with an Exchanged Heme Ligand

Czjzek, Mirjam; Létoffé, Sylvie; Wandersman, Cécile; Delepierre, Muriel; Lecroisey, Anne; Izadi-Pruneyre, Nadia

doi:10.1016/j.jmb.2006.10.063

Cited by 43 publications

(33 citation statements)

References 32 publications

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“…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).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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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“…Because fresh ferric heme exists predominantly as a dimer species in aqueous solutions at physiological pH, HusA binding to this entity may induce dimerization of the protein as observed. Interestingly, S. marcescens was reported to secrete a dimeric form of the hemophore HasA (DHasA) in response to iron deficiency conditions (14). DHasA with two heme molecules ligated at high affinity serves the function of a heme reservoir in this organism (14).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, S. marcescens was reported to secrete a dimeric form of the hemophore HasA (DHasA) in response to iron deficiency conditions (14). DHasA with two heme molecules ligated at high affinity serves the function of a heme reservoir in this organism (14). Compared with other heme-binding proteins found in P. gingivalis, HusA was shown to have a much higher affinity at 7.0 Ϯ 2.5 ϫ 10 Ϫ10 M for the cofactor (more than 1,000 times higher than HmuY with K d ϭ ϳ3 ϫ 10 Ϫ6 M).…”

Section: Discussionmentioning

confidence: 99%

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Characterization of a Hemophore-like Protein from Porphyromonas gingivalis

Gao

Nguyen

Hunter

2010

Journal of Biological Chemistry

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The porphyrin auxotrophic pathogen Porphyromonas gingivalis obtains the majority of essential iron and porphyrin from host hemoproteins. To achieve this, the organism expresses outer membrane gingipains containing cysteine proteinase domains linked to hemagglutinin domains. Heme mobilized in this way is taken up by P. gingivalis through a variety of potential portals where HmuY/HmuR of the hmu locus are best described. These receptors have relatively low binding affinities for heme. In this report, we describe a novel P. gingivalis protein, HusA, the product of PG2227, which rapidly bound heme with a high binding constant at equilibrium of 7 ؋ 10 ؊10 M. HusA is both expressed on the outer membrane and released from the organism. Spectral analysis indicated an unusual pattern of binding where heme was ligated preferentially as a dimer. Further, the presence of dimeric heme induced protein dimer formation. Deletional inactivation of husA showed that expression of this moiety was essential for growth of P. gingivalis under conditions of heme limitation. This finding was in accord with the pronounced increase in gene expression levels for husA with progressive reduction of heme supplementation. Antibodies reactive against HusA were detected in patients with chronic periodontitis, suggesting that the protein is expressed during the course of infection by P. gingivalis. It is predicted that HusA efficiently sequesters heme from gingipains and fulfills the function of a high affinity hemophorelike protein to meet the heme requirement for growth of P. gingivalis during establishment of infection.

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Hemophore Has A

Izadi-Pruneyre¹,

Wolff²,

Delepierre³

et al. 2004

Handbook of Metalloproteins

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To satisfy their iron needs, several gram‐negative bacteria use a heme uptake system that relies on the secretion in the extracellular medium of heme‐binding proteins called HasA hemophores . These proteins scavenge heme from the host, either free or hemoprotein‐bound, and shuttle it to a specific outer membrane transporter, HasR, whereby it is internalized by a TonB‐dependent process and then used as an iron source. HasA hemophores form a family of highly conserved 19–20 kDa proteins without either sequential or structural similarities to other known proteins. The HasA hemophore from Serratia marcescens , the most deeply studied, is described here with a special focus on its heme binding site and its unusual pair of axial ligands, a histidine and a tyrosine. The spectroscopic properties and the structures of the heme loaded and unloaded hemophore, free or complexed to the HasR transporter are presented. The mechanisms of heme capture by the hemophore and heme transfer to HasR are discussed.

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The Crystal Structure of the Secreted Dimeric Form of the Hemophore HasA Reveals a Domain Swapping with an Exchanged Heme Ligand

Cited by 43 publications

References 32 publications

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

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

Characterization of a Hemophore-like Protein from Porphyromonas gingivalis

Hemophore Has A

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