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Title:Toxin-membrane interactions of Pasteurella multocida toxin and homologous domains
Author(s):Brothers, Michael
Director of Research:Rienstra, Chad M.; Wilson, Brenda A.
Doctoral Committee Chair(s):Rienstra, Chad M.; Wilson, Brenda A.
Doctoral Committee Member(s):Mitchell, Douglas A.; Blanke, Steven R.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Nuclear magnetic resonance (NMR) spectroscopy
Pasteurella multocida toxin
Membrane Localization Domain
Four Helix Bundle
Abstract:Toxin-membrane interactions are poorly understood on the molecular level due to the inherent difficulty of crystallizing membrane protein complexes and the large size (>50 kDa) of most functional AB or MARTX protein toxins. Toxins can interact with membranes at three stages during intoxication: 1) receptor binding to the cell surface, 2) membrane translocation, and/or 3) intracellular membrane targeting. To understand the intoxication process, it is necessary to develop an understanding of the structures, dynamics, and mechanisms through which toxins interact with membranes. In this thesis, we focus on the membrane-binding domains of Pasteurella multocida toxin, a 144-kDa dermonecrotic AB-type toxin that causes atrophic rhinitis, and homologous domains in other toxins. We address both the N-terminal domain necessary for receptor-mediated endocytosis into the cell, as well as the intracellular membrane localization domain (MLD), which is believed to be necessary to enable proper targeting of the catalytic domain for cytotoxicity. We demonstrate that the N-terminal receptor-binding domain preferentially binds to the membrane component sphingomyelin and a putative co-receptor (chapter 2), that the MLD undergoes a secondary-structure conformational change upon membrane interaction (chapter 3), and that this phenomenon has pH-dependent dynamics that may enable the MLD to survive the endosome before it becomes functional at cytosolic pH (chapter 4). This thesis provides a framework for understanding the topology and chemistry behind toxin-membrane interactions.
Issue Date:2014-05-30
Rights Information:Copyright 2014 Michael Brothers
Date Available in IDEALS:2014-05-30
Date Deposited:2014-05

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