Functional roles and underlying mechanism of site-specific N-terminal phosphorylation in a heterotrimeric G protein gamma subunit
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Nassiri Toosi, Zahra
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Abstract
Heterotrimeric G-proteins (consisting of Ga, Gb, and Gg subunits) transduce extracellular signals such as hormones and neurotransmitters into intracellular responses that enable cells to communicate with their environment. Dysregulation of G-protein signaling pathways have significant implications in cardiovascular disease, diabetes, and cancer. Therefore, understanding the underlying signaling and regulatory mechanisms of the G-protein signaling systems is of prime importance. While several regulatory roles have been associated with Ga and Gb subunits, Gg subunits, the smallest components of the heterotrimeric G-protein complex, have been long recognized solely as membrane anchors for Gb subunits. Here, I will demonstrate a novel regulatory role for Gg subunits that is mediated through combinatorial phosphorylation of their intrinsically disordered N-terminal (Nt) tails. Using the yeast model system, I show that the Gg subunit (Ste18) undergoes multi-site phosphorylation within its disordered Nt tail in response to a range of different stimuli, such as G-protein activation and cellular stress. Phosphorylation exhibits inter-site interactivity that is controlled by multiple kinases that produce differential effects on the structure and function of Ste18-Nt subunits and output from the G-protein signaling pathway. Taken together, my work sheds light on a new multi-site phosphorylation code in Gg subunits that facilitates their function as governors of G-protein signaling. Similar such codes have been described for other important proteins including histones, RNA polymerases, and G protein coupled receptors, thus placing Gg subunits among the list of intrinsically disordered proteins that exploit combinatorial post-translational modification to govern signaling pathway outputs.
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2021-04-22
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Dissertation