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Title page for ETD etd-04072008-141141


Type of Document Dissertation
Author Oldham, William Michael
Author's Email Address wm.oldham@gmail.com
URN etd-04072008-141141
Title Mapping Conformational Changes Along the Activation Pathway of the Heterotrimeric G Protein α Subunit with Site-directed Spin-labeling
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Vsevolod Gurevich Committee Chair
Hassane Mchaourab Committee Member
Heidi E. Hamm Committee Member
Jeff Conn Committee Member
Keywords
  • heterotrimer
  • GPCR
  • rhodopsin
  • transducin
Date of Defense 2006-06-08
Availability unrestricted
Abstract
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.
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