Abstract
The heme acquisition machinery in Group A Streptococcus (GAS) consists of the surface proteins Shr and Shp and ATP-binding cassette transporter HtsABC. Shp cannot directly acquire heme from methemoglobin (metHb) but directly transfers its heme to HtsA. It has not been previously determined whether Shr directly relays heme from metHb to Shp. Thus, the complete pathway for heme acquisition from metHb by the GAS heme acquisition machinery has remained unclear. In this study, the metHb-to-Shr and Shr-to-Shp heme transfer reactions were characterized by spectroscopy, kinetics and protein-protein interaction analyses. Heme is efficiently transferred from the β and α subunits of metHb to Shr with rates that are 7 and 60 times greater than those of the passive heme release from metHb, indicating that Shr directly acquires heme from metHb. The rapid heme transfer from Shr to Shp involves an initial heme donor/acceptor complex and a spectrally and kinetically detectable transfer intermediate, implying that heme is directly channeled from Shr to Shp. The present results show that Shr speeds up heme transfer from metHb to Shp, whereas Shp speeds up heme transfer from Shr to HtsA. Furthermore, the findings demonstrate that Shr can interact with metHb and Shp but not HtsA. Taken together with our published results on the Shp/HtsA reaction, these findings establish a model of the heme acquisition pathway in GAS in which Shr directly extracts heme from metHb and Shp relays it from Shr to HtsA.
Highlights
Iron is an essential nutrient for growth and survival of most bacterial pathogens
Heme transfer from metHb to apoShr We previously developed a method to demonstrate whether a hemoprotein directly transfers its heme to another protein
This study reports four findings regarding the pathway for heme acquisition from metHb by the Shr/Shp/HtsABC system
Summary
Iron is an essential nutrient for growth and survival of most bacterial pathogens. The sources of iron in vivo for bacteria are host hemoproteins, such as hemoglobin (Hb), haptoglobin, and hemopexin, non-heme iron-protein complex transferrin, and other iron complexes [1]. Heme is a major source of iron for bacterial pathogens. Some bacteria produce hemophore to sequester heme from host hemoproteins [2,3]. Heme can be directly sequestered from host proteins by receptors on the bacterial surface [4,5,6]. Captured heme is transported across the outer membrane by a TonB-dependent process in Gram-negative bacteria [7] or is relayed through the cell wall by surface proteins in Gram-positive pathogens [8,9]. ATP-binding cassette (ABC) transporters transport heme across the cytoplasmic membrane
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