Host-Pathogen Interactions: Heme-Iron Acquisition

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To successfully mount infections bacterial pathogens actively procure iron from their human host, which is extremely scarce because of nutritional immunity mechanisms. Hemoglobin within erythrocytes is an attractive source of iron, as it contains ~75-80% of the body’s total iron in the form of heme (iron-protoporphyrin IX). In ongoing research, we studying the molecular mechanisms used by Gram-positive bacteria to remove hemoglobin’s heme molecule, the first step gaining access to this rich nutrient source. In collaborative studies we are applying computational and experimental methodologies to decipher the structural, dynamic and energetic basis through which the S. aureus IsdH protein extracts heme from human hemoglobin (Hb). This process is highly conserved and used by many bacterial species to obtain the essential nutrient iron. Recent structural data and newly developed experimental tools make IsdH a powerful model system in which to explore the heme extraction mechanism.








Relevant References:

Sjodt M, Macdonald R, Marshall JD, et al. Energetics Underlying Hemin Extraction from Human Hemoglobin by Staphylococcus aureus. J Biol Chem. 2018. doi:10.1074/jbc.RA117.000803.

Claire F, Dickson CF, Jacques D, Clubb RT, Guss JM and Gell DA. The structure of haemoglobin bound to the haemoglobin-receptor, IsdH, from Staphylococcus aureus shows disruption of the native alpha-globin haem pocket. Acta Crystallogr D Biol Crystallogr. 2015 Jun;71(Pt 6):1295-306. 

Sjodt M, Macdonald R, Spirig T, Chan AH, Dickson CF, Fabian M, Olson JS, Gell DA and Clubb RT. The PRE-derived NMR model of the 38.8-kDa tri-domain IsdH protein from Staphylococcus aureus suggests that it adaptively recognizes human hemoglobin. J Mol Biol. 2015 Feb 14. [Epub ahead of print]

Malmirchegini GR, Sjodt M, Shnitkind S, Sawaya MR, Rosinski J, Newton SM, Klebba PE, Clubb RT. Novel mechanism of hemin capture by Hbp2, the hemoglobin-binding hemophore from Listeria monocytogenes. J Biol Chem. 2014 Dec 12;289(50):34886-99

Dickson CF, Krishna Kumar K, Jacques DA, Malmirchegini GR, Spirig T, Mackay JP, Clubb RT, Guss JM, Gell DA. Structure of the Hemoglobin-IsdH Complex Reveals the Molecular Basis of Iron Capture by Staphylococcus aureus. J Biol Chem. 2014 Jan 14. [Epub ahead of print]

Ran Y, Malmirchegini GR, Clubb RT, Lei B. Axial ligand replacement mechanism in heme transfer from streptococcal heme-binding protein Shp to HtsA of the HtsABC transporter. Biochemistry 52(37) 2013; 6537-47. doi: 10.1021/bi400965u. [Epub ahead of print]..

Spirig T, Malmirchegini GR, Zhang J, Robson SA, Sjodt M, Liu M, Krishna Kumar K, Dickson CF, Gell DA, Lei B, Loo JA, Clubb RT. Staphylococcus aureus uses a novel multidomain receptor to break apart human hemoglobin and steal its heme. J Biol Chem. 288(2) 2013; 1065-78.

Kumar KK, Jacques DA, Pishchany G,Caradoc-Davies T, Spirig T, Malmirchegini GR, Langley DB, Dickson CF, Mackay JP, Clubb RT, Skaar EP, Guss MJ, and Gell DA. The structural basis for hemoglobin capture by the Staphylococcus aureus cell-surface protein, IsdH. Journal of Biological Chemistry 44  2011; 38439-47

Villareal VA, Spirig T, Robson SA, Liu M, Lei B, and Clubb RT. Transient Weak Protein-Protein Complexes Transfer Heme Across the Cell Wall of Staphylococcus aureus. Journal of the American Chemical Society 133 2011; 14176-9.