GPCR signaling: conformational activation of arrestins

Arrestin Recruitment to C-C Chemokine Receptor 5: Potent C-C Chemokine Ligand 5 Analogs Reveal Differences in Dependence on Receptor Phosphorylation and Isoform-Specific Recruitment Bias

“…According to the current model (Eichel et al, 2018;Kahsai et al, 2018;, arrestins use two mechanisms to interact with activated GPCRs. The 'tail interaction' involves destabilization of an internal ionic lock in the arrestin protein by the negatively charged phosphorylated C-terminal tail region of the receptor, leading to a conformational change in the arrestin protein that enables it to stably interact with the receptor C-terminal tail region (Eichel et al, 2018;Kahsai et al, 2018;Latorraca et al, 2018), and the 'core interaction' involves docking of a conformationally flexible structure on the arrestin protein with structural motifs conserved across the GPCR superfamily that are revealed upon receptor activation (Eichel et al, 2018;Kahsai et al, 2018;Latorraca et al, 2018).…”

“…According to the current model (Eichel et al, 2018;Kahsai et al, 2018;, arrestins use two mechanisms for recruitment to activated GPCRs. The 'tail interaction' involves destabilization of an internal ionic lock in the arrestin protein by the phosphorylated C-terminal tail region of the receptor, resulting in a conformational change that stabilizes binding to this region of the receptor (Eichel et al, 2018;Kahsai et al, 2018;Latorraca et al, 2018).…”

“…The 'tail interaction' involves destabilization of an internal ionic lock in the arrestin protein by the phosphorylated C-terminal tail region of the receptor, resulting in a conformational change that stabilizes binding to this region of the receptor (Eichel et al, 2018;Kahsai et al, 2018;Latorraca et al, 2018). The 'core interaction' involves docking of a conformationally flexible structure on the arrestin protein with structural motifs revealed upon receptor activation that are conserved across the GPCR superfamily (Eichel et al, 2018;Kahsai et al, 2018;Latorraca et al, 2018). Previously published work has indicated that both the enhanced receptor internalization elicited by PSC-RANTES (Escola et al, 2010;Gaertner et al, 2008) and the modified post-endocytic trafficking itinerary driven by 5P14-RANTES (Bönsch et al, 2015) might be explained by differences in the extent and duration of arrestin recruitment, but the molecular mechanisms underlying these differences have yet to be elucidated.…”

Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1

“…With this notion, the study of these molecular transducers has been approached by some authors in recent years from a top-down point of view, whereby sub-type specific, allosteric positive or negative modulators (PAM, NAMs), as well as direct agonists, are utilized as tools for pathway dissection and analysis ( 63 , 64 ). In the last decade, technological advancements in techniques such as circular dichroism ( 65 ), Cryo-electron microscopy (Cryo-EM) ( 66 ) and crystallography ( 67 ) have expanded our understanding of the physiology of multiple chemosensors expressed by L-cells, which led to the discovery of new molecular tools with possible future clinical applications in diseases such as type 2 diabetes ( 64 , 68 – 70 ).…”

GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses

“…GDP, guanosine diphosphate; GTP, guanosine triphosphate α γ β β β γ γ α α dependent or independent manner, adds an additional layer of complexity into the signaling mechanisms (desensitization) between activation of GPCRs and a variety of effectors seen in different cell types. [39][40][41] Understanding of the coupling of GPR91 with different G protein subunits will facilitate the delineation of downstream molecular interactions in different cell types in responses to a variety of metabolic and inflammatory microenvironment changes. In summary, the change of succinate concentration acts as a metabolic regulation in steatotic hepatocytes (activation of HSCs), autoimmunity (dendritic cell activation and anti-inflammation phenotype of macrophage), and oncogenic metabolism (glycolytic metabolism and angiogenesis).…”