Cryo-EM undiscloses structural and mechanistic details on iron hijacking by Staphylococcus aureus: An insight into the interaction of IsdB hemophore with human hemoglobin

Iron is an essential nutrient for almost all organisms. In the human body, it is primarily bound to the heme cofactor of hemoglobin (Hb), myoglobin and other heme-binding proteins. During infection, Staphylococcus aureus exploits Hb heme pool as its favored iron source, capturing and internalizing it by cell wall hemophores. The first step is performed by IsdB, which intercepts free Hb and extracts heme. IsdB, a proven virulence factor, is an attractive putative target for antimicrobials development but its mechanism of action needs to be further detailed. To this aim, we used cryo-EM single-particle analysis to study IsdB:Hb complex formation and heme extraction. The key complexes before and after heme extraction were solved at 2.9 angstrom and 5.8 angstrom resolution using carboxyHb, resistant to heme removal, and oxidized Hb, the physiologic IsdB substrate. IsdB first binds to Hb beta -chains, enhancing Hb dimerization to favor a second IsdB molecule binding to alpha -chains before extraction. These results greatly improve our current knowledge