Using Allosteric Transition Models to Gain Insight on the Signaling Response of Membrane Modulated Proteins
2016-07
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Using Allosteric Transition Models to Gain Insight on the Signaling Response of Membrane Modulated Proteins
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2016-07
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The signaling response of membrane modulated proteins are influenced by their complex lipid environments. To further understand the mechanistic role of their signaling response and the influence of their environment, the structure and functionality of membrane protein systems were studied. Synaptotagmin I (Syt 1) is a vesicle-localized integral membrane protein that sense calcium ions (Ca2+) for neuronal exocytosis. The utilization of the cytosolic domains and the role of the intrinsically disordered region (IDR) between Syt I’s transmembrane helix and first C2 domain (C2A) in the allosteric communication and modulation of Ca2+ binding are poorly understood. Using differential scanning calorimetry (DSC), nuclear magnetic resonance, and isothermal titration calorimetry (ITC), the structure of the IDR and allosteric modulation of Ca2+ on Syt I’s C2A investigated. Annexins are a large class of membrane binding proteins which are found in all eukaryotic cells and are capable of both sensing membrane damage and orchestrating its repair by means of Ca2+ and membrane binding. Annexin a5 is one of many annexins found in muscle cells, and is known to have a mechanistic role in membrane repair. The inability of the cell to repair its membrane after damage causes forms of muscular dystrophy, and it is this repair process that is poorly understood. Using DSC and ITC, the impact of mole fraction of cholesterol within the membrane was studied. Epidermal Growth Factor Receptor (erbB1) is a transmembrane receptor tyrosine kinase that is implicated in normal cellular growth and development. Mutation and/or overexpression of erbB1 can lead to constitutive activity resulting in uncontrolled cellular proliferation. Using single particle tracking of quantum dot-labeled receptors in the plasma membrane of live cells, receptor mobility and interactions were observed in real time. Through analysis of these trajectories, an allosteric transition model was developed to provide a new understanding on the effect of lipid ordering on the conformational distribution and behavior of erbB1.
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University of Minnesota M.S. thesis. July 2016. Major: Chemistry. Advisor: Anne Hinderliter. 1 computer file (PDF); x, 106 pages.
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Kobany, Stephanie. (2016). Using Allosteric Transition Models to Gain Insight on the Signaling Response of Membrane Modulated Proteins. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/190591.
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