Heme binding in the NEAT domains of IsdA and IsdC of Staphylococcus aureus

Pluym, Mark; Muryoi, Naomi; Heinrichs, David E.; Stillman, Martin J.

doi:10.1016/j.jinorgbio.2007.11.011

Cited by 47 publications

(73 citation statements)

References 18 publications

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“…S1). First, with respect to the ␤-hairpin region, the first tyrosine of the YXXXY signature sequence is thought to be the fifth axial ligand and coordinates the heme iron, a result confirmed in the crystal structures of IsdC and IsdA and supported by mutagenesis data (42,46,48). The second tyrosine probably stabilizes this linkage by hydrogen bonding to the first.…”

Section: Discussionmentioning

confidence: 78%

“…1A). A comparison of each NEAT indicates that four of the five NEATs contain a YXXXY sequence within the proposed hemebinding pocket (8,16,(45)(46)(47) (Fig. 1A, red text, and supplemental Fig.…”

Section: In Silico Analysis Of Isdx2 and Protein Purification-mostmentioning

confidence: 99%

“…This strategy simplifies the assignment of a function to a single domain, avoids the use of full-length IsdX2 (which is difficult to purify because of its susceptibility to proteolysis), and is consistent with existing literature that indicates individual NEAT domains form functional units (41, 42, 46 -50). B. anthracis genomic DNA encoding each NEAT was amplified by PCR and cloned into pGEX2TK to create a fusion to GST (15,16,30,41,42,45,46,49,(51)(52)(53). Recombinant GST-NEATn protein was expressed in E. coli and purified by affinity chromatography, and each NEAT domain was released from GST by thrombin proteolysis.…”

Section: In Silico Analysis Of Isdx2 and Protein Purification-mostmentioning

confidence: 99%

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The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC

Honsa

Fabián

Cárdenas

et al. 2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 78%

Section: In Silico Analysis Of Isdx2 and Protein Purification-mostmentioning

confidence: 99%

Section: In Silico Analysis Of Isdx2 and Protein Purification-mostmentioning

confidence: 99%

See 1 more Smart Citation

The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC

Honsa

Fabián

Cárdenas

et al. 2011

Journal of Biological Chemistry

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“…IsdH and IsdB likely function as hemoglobin receptors and partake in heme extraction from hemoglobin (16,17,65,81). Heme is next passed to IsdA and IsdC, two additional cell wall-anchored proteins, which subsequently transfer the heme to the membrane protein IsdE (26,41,50,57,66,67,80,82,86). Finally, IsdE likely passes heme to the monooxygenase IsdG, where enzymatic degradation of the heme yields free iron and biliverdin (72,73).…”

Section: Discussionmentioning

confidence: 99%

“…Both IsdX1 and IsdX2 harbor near iron transporter domains (NEATs), a conserved protein module found in Gram-positive bacteria that mediates heme uptake from hemoglobin and contributes to bacterial pathogenesis upon infection (3,8,21,31,44,46,49,50,67,81,86). Hypothesizing that B. anthracis may contain additional mechanisms for heme transport, we provide evidence that B. anthracis S-layer protein K (BslK), an S-layer homology (SLH) and NEAT protein (32,43), is surface localized and binds and transfers heme to IsdC in a rapid, contact-dependent manner.…”

mentioning

confidence: 99%

ABacillus anthracisS-Layer Homology Protein That Binds Heme and Mediates Heme Delivery to IsdC

et al. 2010

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The sequestration of iron by mammalian hosts represents a significant obstacle to the establishment of a bacterial infection. In response, pathogenic bacteria have evolved mechanisms to acquire iron from host heme. Bacillus anthracis, the causative agent of anthrax, utilizes secreted hemophores to scavenge heme from host hemoglobin, thereby facilitating iron acquisition from extracellular heme pools and delivery to iron-regulated surface determinant (Isd) proteins covalently attached to the cell wall. However, several Gram-positive pathogens, including B. anthracis, contain genes that encode near iron transporter (NEAT) proteins that are genomically distant from the genetically linked Isd locus. NEAT domains are protein modules that partake in several functions related to heme transport, including binding heme and hemoglobin. This finding raises interesting questions concerning the relative role of these NEAT proteins, relative to hemophores and the Isd system, in iron uptake. Here, we present evidence that a B. anthracis S-layer homology (SLH) protein harboring a NEAT domain binds and directionally transfers heme to the Isd system via the cell wall protein IsdC. This finding suggests that the Isd system can receive heme from multiple inputs and may reflect an adaptation of B. anthracis to changing iron reservoirs during an infection. Understanding the mechanism of heme uptake in pathogenic bacteria is important for the development of novel therapeutics to prevent and treat bacterial infections.

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Selective binding of antimicrobial porphyrins to the heme‐receptor IsdH‐NEAT3 of Staphylococcus aureus

Moriwaki

Caaveiro

et al. 2013

Protein Science

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The Isd (iron-regulated surface determinant) system of the human pathogen Staphylococcus aureus is responsible for the acquisition of heme from the host organism. We recently reported that the extracellular heme receptor IsdH-NEAT3 captures and transfers noniron antimicrobial porphyrins containing metals in oxidation state (III). However, it is unclear if geometric factors such as the size of the metal (ionic radius) affect binding and transfer of metalloporphyrins. We carried out an ample structural, functional, and thermodynamic analysis of the binding properties of antimicrobial indium(III)-porphyrin, which bears a much larger metal ion than the iron(III) of the natural ligand heme. The results demonstrate that the NEAT3 receptor recognizes the In(III)-containing PPIX in a manner very similar to that of heme. Site-directed mutagenesis identifies Tyr642 as the central element in the recognition mechanism as suggested from the crystal structures. Importantly, the NEAT3 receptor possesses the remarkable ability to capture dimers of metalloporphyrin. Molecular dynamics simulations reveal that IsdH-NEAT3 does not require conformational changes, or large rearrangements of the residues within its binding site, to accommodate the much larger (heme) 2 ligand. We discuss the implications of these findings for the design of potent inhibitors against this family of key receptors of S. aureus.

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Heme binding in the NEAT domains of IsdA and IsdC of Staphylococcus aureus

Cited by 47 publications

References 18 publications

The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC

The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC

ABacillus anthracisS-Layer Homology Protein That Binds Heme and Mediates Heme Delivery to IsdC

Selective binding of antimicrobial porphyrins to the heme‐receptor IsdH‐NEAT3 of Staphylococcus aureus

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