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dc.contributor.advisorTesmer, Johnen
dc.creatorLodowski, David Thomasen
dc.date.accessioned2008-08-28T21:57:25Zen
dc.date.available2008-08-28T21:57:25Zen
dc.date.issued2004en
dc.identifierb59327765en
dc.identifier.urihttp://hdl.handle.net/2152/1359en
dc.descriptiontexten
dc.description.abstractThe sensations of sight, smell, and taste as well as the regulation of heart rate, blood pressure, and glucose metabolism are all controlled by a family of proteins known as the heterotrimeric G proteins. The heterotrimeric G proteins are made up of a Gα, and a constitutive dimer of Gβ and Gγ. These heterotrimeric G proteins function to transmit a signal generated by the binding of an agonist (hormone) to a G protein-coupled receptor (GPCR) to G protein effector proteins within the cell. This binding event initiates a structural change within the GPCR which triggers a structural change within the Gα subunit and triggers the release of the Gα and Gβγ subunits. This conformational change within the Gα subunit leads an exchange of GDP for GTP and allows the Gα subunit to regulate the activities of downstream signaling proteins such as adenylyl cyclase and other signaling proteins. Upon activation of Gα, the Gβγ subunits also associate with and regulate G protein effectors such as Gprotein-coupled receptor kinases (GRKs), phospholipases, and signaling proteins. In order that cells can rapidly adapt to changes in their external (extracellular) environments, previously stimulated GPCRs must be quickly desensitized. This process is initiated by GRKs, enzymes that phosphorylate the cytoplasmic loops of activated GPCRs. This phosphorylation event tags the GPCR for binding by proteins called arrestins, which upon binding block further activation of heterotrimeric G protein subunits and initiates recycling or degradation via clathrin mediated endocytosis. To gain a better understanding of the role that the GRKs play in the regulation of the signals that are transmitted through GPCRs, we have crystallized and solved the structures of GRK2 alone and in complex with the heterotrimeric G proteins Gβ1γ2. These structures reveal the orientations and interactions of the individual domains within GRK2. Furthermore, the domain structure and the Gβ1γ2 binding surfaces reveal both the mechanism of recruitment to the membrane as well as suggesting possible routes for the allosteric activation of GRK2 by Gβ1γ2 and phospholipids.
dc.format.mediumelectronicen
dc.language.isoengen
dc.rightsCopyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.en
dc.subject.lcshG proteinsen
dc.titleStructural basis for the regulation of GRK2 by G[beta][gamma]en
dc.description.departmentInstitute for Cellular and Molecular Biologyen
dc.identifier.oclc57894608en
dc.identifier.proqst3150683en
dc.type.genreThesisen
thesis.degree.departmentCellular and Molecular Biology, Institute foren
thesis.degree.disciplineMolecular Biologyen
thesis.degree.grantorThe University of Texas at Austinen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen


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