Directed Inter-domain Motions Enable the IsdH Staphylococcus aureus Receptor to Rapidly Extract Heme from Human Hemoglobin |
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| Institution: | 1. Department of Physics and Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, IL 60616, USA;2. UCLA Department of Chemistry and Biochemistry, University of California, Los Angeles, 611 Charles Young Drive East, Los Angeles, CA 90095, USA;3. UCLA-DOE Institute of Genomics and Proteomics, University of California, Los Angeles, 611 Charles Young Drive East, Los Angeles, CA 90095, USA;4. Molecular Biology Institute, University of California, Los Angeles, 611 Charles Young Drive East, Los Angeles, CA 90095, USA;1. Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel;2. Department of Plant Molecular Biology, Lausanne University, 1015 Lausanne, Switzerland;1. Institute of Biochemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany;2. Department of Life Sciences and Chemistry, Jacobs University Bremen, 28719 Bremen, Germany;3. Center for Structural Studies Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany;4. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany;5. Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom;6. Institute for Medical Physics and Biophysics and Center for Soft Nanoscience, Westfälische Wilhelms Universität Münster, 48149 Münster, Germany;7. Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany;1. Proteomics and Structural Biology Unit, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110025, India;2. Academy of Scientific and Innovative Research, CSIR-HRDG, Ghaziabad, Uttar Pradesh 201002, India;3. CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India;4. Centre for Computational Biology, Indraprastha Institute of Information Technology, New Delhi 110020, India;5. Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, Gautam Buddha Nagar, Uttar Pradesh 201314, India;1. School of Pharmacy, University of Nottingham, East Drive, University Park, Nottingham NG7 2RD, UK;2. Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia;3. Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester, Leicester LE1 7RH, UK |
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| Abstract: | Pathogenic Staphylococcus aureus actively acquires iron from human hemoglobin (Hb) using the IsdH surface receptor. Heme extraction is mediated by a tri-domain unit within the receptor that contains its second (N2) and third (N3) NEAT domains joined by a helical linker domain. Extraction occurs within a dynamic complex, in which receptors engage each globin chain; the N2 domain tightly binds to Hb, while substantial inter-domain motions within the receptor enable its N3 domain to transiently distort the globin’s heme pocket. Using molecular simulations coupled with Markov modeling, along with stopped-flow experiments to quantitatively measure heme transfer kinetics, we show that directed inter-domain motions within the receptor play a critical role in the extraction process. The directionality of N3 domain motion and the rate of heme extraction is controlled by amino acids within a short, flexible inter-domain tether that connects the N2 and linker domains. In the wild-type receptor directed motions originating from the tether enable the N3 domain to populate configurations capable of distorting Hb’s pocket, whereas mutant receptors containing altered tethers are less able to adopt these conformers and capture heme slowly via indirect processes in which Hb first releases heme into the solvent. Thus, our results show inter-domain motions within the IsdH receptor play a critical role in its ability to extract heme from Hb and highlight the importance of directed motions by the short, unstructured, amino acid sequence connecting the domains in controlling the directionality and magnitude of these functionally important motions. |
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| Keywords: | iron-regulated surface determinant system hemoglobin receptor stopped-flow spectrophotometry molecular dynamics NEAT"} {"#name":"keyword" "$":{"id":"k0035"} "$$":[{"#name":"text" "_":"NEAr iron Transporter Hb"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"hemoglobin |
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