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• W2346373755 abstract "G protein-coupled receptors (GPCRs) are a superfamily of seven transmembrane receptors that respond to a diverse array of stimuli, regulate a multitude of physiological responses and are the targets of most drugs used clinically. Activated GPCRs undergo conformational changes, facilitating activation of specific heterotrimeric G protein subtypes by functioning as a guanine-nucleotide exchange factor (GEF) facilitating exchange of GDP for GTP on the G[alpha] subunit resulting in dissociation of [beta][gamma] subunits and downstream signaling. GPCR signal termination is mediated by desensitization and internalization. Interestingly, certain GPCRs have the capacity to couple to multiple distinct G protein subtypes even in the same cell. However, the mechanisms that specify GPCR-G protein coupling to specific subtypes remains poorly understood. Many GPCRs are modified by N- linked glycosylation but whether this modification contributes to GPCR signal regulation has yet to be fully explored. In the work described in the thesis I examined whether N-linked glycosylation of protease-activated receptor-1 (PAR1), a GPCR for the coagulant protease thrombin, regulated receptor function. I found that PAR1 is extensively glycosylated on the N-terminus and extracellular loop two (ECL2), with ECL2 serving as the major site for N-linked glycosylation. I also discovered that N-linked glycosylation of PAR1 at the N-terminus is important for transport to the cell surface, whereas glycosylation at ECL2 makes important contributions to receptor activation. Activation of PAR1 occurs via proteolytic cleavage of the N-terminus resulting in the generation of a new N-terminus, which functions as a tethered ligand by binding intramolecularly to ECL2 to facilitate transmembrane signaling. I discovered that N- linked glycosylation at ECL2 regulates G protein coupling specificity. PAR1 wild-type displayed preferential coupling to G₁₂/₁₃ versus Gq, whereas a PAR1 mutant lacking N-linked glycosylation at ECL2 exhibited enhanced coupling to Gq versus G₁₂/₁₃ . Intriguingly, both PAR1 wild-type and mutant coupled comparably to Gi protein. In summary, the work in this thesis describes a function for N-linked glycosylation of PAR1 in regulating receptor-G protein coupling specificity and provides the first molecular insight into mechanisms that can influence activated GPCR biased coupling to specific G protein subtypes" @default.
• W2346373755 created "2016-06-24" @default.
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• W2346373755 date "2013-01-01" @default.
• W2346373755 modified "2023-09-24" @default.
• W2346373755 title "N-linked glycosylation regulates protease-activated receptor-1 trafficking and signaling" @default.
• W2346373755 hasPublicationYear "2013" @default.
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