The University of Kansas
Mechanisms of Heme Capture by the Hemophore Secreted by Pseudomonas aeruginosa (2008)
Heme is the most abundant source of circulating iron in mammals. It is therefore not surprising that many pathogenic bacteria, including the opportunistic Pseudomonas aeruginosa, avidly pursue its capture and internalization in order to overcome the very low free-iron concentrations encountered in their mammalian hosts. To capture heme, several pathogenic bacteria, including P. aeruginosa, deploy a heme acquisition system (Has), which consists of a protein secreted to the extracellular space (HasAp) and an outer membrane receptor (HasR). HasAp is also termed a hemophore because it efficiently captures hemoglobinheme and delivers it to the receptor for subsequent internalization.
The studies proposed herein aim to achieve fundamental molecular level understanding of the protein-protein interactions that allow HasAp to “steal” heme from human hemoglobin. In particular, the investigators seek to gain unprecedented structural, dynamic and mechanistic insights into the factors that determine the transfer of heme from human hemoglobin to HasAp.
This long-range goal will be reached by pursuing two main objectives:
- Elucidate the three dimensional structure of apo-HasAp,
- Identify the binding interface of the encounter complex that forms when HasAp binds to hemoglobin, prior to heme transfer, and decipher the role played by the gross reorganization of HasAp structural elements in the molecular recognition and binding to hemoglobin.