Wißbrock, Amelie: Transient Heme-Protein Interactions: Structural and Functional Studies on Interleukin-36α and Amyloid-β. - Bonn, 2020. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-59404
@phdthesis{handle:20.500.11811/8547,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-59404,
author = {{Amelie Wißbrock}},
title = {Transient Heme-Protein Interactions: Structural and Functional Studies on Interleukin-36α and Amyloid-β},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2020,
month = aug,

note = {The porphyrin heme is primarily known as a pivotal blood component. As functional part of hemoglobin, heme is responsible for the blood’s vibrant red color and enables the transport of oxygen within the body. Moreover, biologically available heme acts as an effector and signaling molecule. As such, heme alters the activity and/or stability of proteins or evokes the formation of catalytically active complexes via transient heme-protein interactions. The latter was first observed for Amyloid beta (Aβ), whose aberrant accumulation is a hallmark of Alzheimer’s disease (AD). Elevated heme levels are increasingly discussed in the context of assorted pathological conditions, such as inflammation and malaria as well as AD. Yet, intra- and extracellular heme concentrations are largely unknown due to the lack of suitable quantification methods. Within the scope of this work, a test system based on the catalytic activity of hemepeptide complexes was established to quantify biologically available heme in patient samples, such as Liquor cerebrospinalis (CSF). Beyond this, a potential interaction of heme with the proinflammatory cytokine interleukin-36α (IL-36α) was investigated.
Initially, a selection of heme-peptide complexes was examined with regard to their catalytic activity. A heme-binding 23mer peptide proved to be superior to Aβ and highly suitable for the application in a heme quantification assay. Subsequent studies with human CSF verified the correlation between substrate conversion and heme concentration. Heme binding to Aβ was characterized in more detail and the possible interplay between heme, the lipoprotein LDL, and Aβ, as it might occur in AD, was analyzed. Besides, a potential heme interaction with the proinflammatory cytokine IL-36α was subject of investigation. By means of different protein mutants and various spectroscopic methods, the binding of two heme molecules to distinct sequence motifs in IL-36α was confirmed. Structural analysis of the cytokine by 3D NMR spectroscopy provided detailed insights into the molecular basis of the hemeprotein interaction. Furthermore, studies with fibroblast-like synoviocytes (FLS) isolated from knee joints of patients with rheumatoid arthritis revealed that heme binding to IL-36α as well as to IL-36β and IL-36γ attenuates IL-36 signaling.
The presented studies on the quantification of heme in patient samples and on the potentially heme-regulated protein IL-36α broaden the existing knowledge on the role of heme as an effector and signaling molecule in medical conditions. Hence, the findings contribute to the general disease understanding as well as to future development of therapy strategies.},

url = {http://hdl.handle.net/20.500.11811/8547}
}

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