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Structural studies of toxins and toxin-like proteins

Aragão Correia, Hugo. Structural studies of toxins and toxin-like proteins. 2016, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12931

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Abstract

Toxins are an ancient mechanism of interaction between cohabiting organisms: basal concentrations serve as an informal cue, enough as a warning signal; too much and the dialog is over. As such, the evolutionary race to arms led to the development of a vast trove of molecular unique biochemical mechanisms, from small molecules to protein toxins. The study of these mechanisms is not only essential for the treatment of toxin-related pathologies, but also as the potential source for novel therapeutic drugs.
In this thesis, a series of studies of different toxins and toxin-like proteins are compiled. To further understand the biological function and relevance of each toxin, their detailed study and characterization were pursued. Here are described the advances made using a combination of different complementary biophysical and structural methods, chosen in each case to specifically target each molecule characteristics. In the first chapter, the general biological theme of this thesis is introduced: toxins, particularly protein toxins, their description, and classification, as well as the role of structural biology in the study of proteins in general. To set the theoretical background of the following chapters, are also described the general principles of two of the most prominent methods for the study of proteins in structural biology: nuclear magnetic resonance (NMR) spectroscopy, and X-ray diffraction. In the second chapter, the interaction between human FKBP12 chaperone protein and two similar bacterial small molecule toxins is detailed: rapamycin initially used as an anti-fungal before the discovery of its potent immunosuppressive properties as a mTOR inhibitor; and mycolactone, a bacterial toxin responsible for the disease Buruli ulcers in humans. In the third chapter, the cell-free protein expression system is introduced as a technique best suited for the expression of cytotoxic proteins and otherwise difficult targets, as explored further in the following chapters. In the fourth chapter, advancements towards the structural and conformational characterization of the membrane-inserted state of two similar pore-forming toxins are detailed: the bacterial Colicin Ia protein; and the human Bax protein, an apoptosis effector; using X-ray crystallography, solution NMR and solid-state NMR. Finally, in the fifth chapter, two FIC-domain bacterial toxins are investigated: the bacterial VbhTA toxin-antitoxin protein complex, and the structural determination with its cognate target, DNA GyraseB enzyme; and the auto-activation of the bacterial NmFIC protein; in both cases using a combination of X-ray crystallography and NMR spectroscopy, as well as other biophysical techniques.
Advisors:Hiller Odermatt, Sebastian and Müller, Daniel J.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
UniBasel Contributors:Aragao Correia, Hugo and Hiller Odermatt, Sebastian
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12931
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (v, 167 Seiten)
Language:English
Identification Number:
Last Modified:25 Jan 2019 05:30
Deposited On:24 Jan 2019 10:41

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