Heterotrimeric G proteins act as molecular switches in signaling pathways by coupling the activation of heptahelical receptors at the cell surface to intracellular responses. These receptors bind to and activate G proteins by catalyzing GTP for GDP exchange on the Gα subunit, leading to a structural change in Gα(GTP) and Gβγ subunits that allows the activation of a variety of downstream effector proteins. Despite its crucial role in a variety of signal transduction pathways, relatively little is known about the structure of the receptor-G protein complex and how this interaction leads to GDP release from Gα. Thus, the primary goal of this research has been to use the biophysical technique of site-directed spin-labeling to identify and characterize receptor-dependent conformational changes in Gα with electron paramagnetic resonance spectroscopy. With this approach, α5 helix of Gα has been shown to play a key role in coupling receptor-binding to GDP release. In addition, the structure and dynamics of several other important regions of this protein have been explored throughout the G protein activation pathway. These studies enhance the current understanding of G protein structure and function, which has been largely based on high resolution structural data from x-ray crystallography, by providing dynamic information about this protein in solution. This combination of structural approaches should continue to provide important insight into the biomechanics of G protein signaling and will hopefully serve as the starting point for more sophisticated models of the critically important receptor-G protein complex.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04072008-141141 |
| Date | 02 May 2008 |
| Creators | Oldham, William Michael |
| Contributors | Jeff Conn, Hassane Mchaourab, Heidi E. Hamm, Vsevolod Gurevich |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-04072008-141141/ |
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