Collaborative Research: Molecular Mechanism of Heme Extraction by IsdH

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In order to establish an infection bacterial pathogens ingest nutrients that enable them to proliferate. Iron is an essential nutrient that is actively acquired by bacteria from human hemoglobin during infections. A key step in microbial iron acquisition is the extraction of iron-laden heme from hemoglobin. Using biophysical and computational approaches the investigators will learn how the pathogen Staphylococcus aureus uses the IsdH surface receptor to extract heme from hemoglobin. This process is clinically important, as it enables methicillin resistant S. aureus (MRSA) to cause infections. The results of this work will provide a detailed view of the mechanism underlying extraction and it will have a broad impact as other bacterial pathogens also use a similar mechanism to acquire iron during infections. The proposal will facilitate undergraduate and graduate student outreach programs of students from under-represented groups at the PhD level. The grant will be used to support outreach efforts to community college students and promote diversity, inclusion, and the elimination of barriers to participation in bioscience research careers.In this project a team of investigators will apply computational and experimental methodologies to decipher the structural, dynamic and energetic basis through which the Staphylococcus 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. The overall goal of this research project is to elucidate how heme is transferred from Hb to IsdH, and to learn how this process is facilitated by inter-domain motions. In Aim #1, simulations and experiments will define the pathway of heme transfer, and uncover specific receptor contacts that facilitate transfer and distort Hb to trigger heme release. In Aim #2, the role of inter-domain motions will be determined by quantitatively assessing their effect on the local concentration of the receptor, and the kinetics and thermodynamics of transfer. Because IsdH is paradigmatic, the results of this project will provide broad insight into the extraction mechanisms used by a wide-range of bacteria.