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Copyright 2014 Michael Brothers Nuclear magnetic resonance (NMR) spectroscopy Pasteurella multocida toxin Membrane Localization Domain Rienstra, Chad M. Wilson, Brenda A. Rienstra, Chad M. Wilson, Brenda A. Mitchell, Douglas A. Blanke, Steven R. Brothers, Michael 2014-05-30T17:17:12Z 2014-05-30T17:17:12Z 2016-09-22T20:59:31Z 2014-05 2014-05-30T17:17:12Z 2014-05 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. Item withdrawn by Laura Spradlin (lspradl2@illinois.edu) on 2013-12-06T22:03:58Z Item was in collections: University of Illinois Theses & Dissertations (ID: 1) No. of bitstreams: 2 Brothers_Michael.docx: 50209971 bytes, checksum: 023eb2b03a1fadf09e4748b411686ad5 (MD5) Brothers_Michael.pdf: 34982467 bytes, checksum: 37ca1168f1d4998d2a846c70028e8bad (MD5) Made available in DSpace on 2014-05-30T17:17:12Z (GMT). No. of bitstreams: 3 Michael_Brothers.pdf: 34990676 bytes, checksum: b87ec480bf49141010fcc04c0c63d39e (MD5) Brothers_Michael.docx: 99576679 bytes, checksum: d3c5fd314caebd11e727a570a5a7109e (MD5) license.txt: 4070 bytes, checksum: 120c822b6ec82e49533710cb98cbc3f5 (MD5) Restriction data tranferred 2014-07-01T11:39:36-05:00 Original Data Group with Access Administrator Release Date: 2016-05-30 12:21:23 UTC Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Item marked as restricted to the 'Administrator' Group (id=1) by Seth Robbins (robbins.sd@gmail.com) on 2014-05-30T17:21:25Z Item is restricted until 2016-05-30T17:21:23Z Limited Restriction Lifted for Item 49828 on 2016-09-22T20:59:31Z. http://hdl.handle.net/2142/49777 en Four Helix Bundle Toxin-membrane interactions of Pasteurella multocida toxin and homologous domains text Chemistry 1413 Chemistry 0335 University of Illinois at Urbana-Champaign Dissertation Ph.D. PHD:Chemistry -UIUC 10KS0335PHD