scholarly journals Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Giovanni Luchetti ◽  
Ria Sircar ◽  
Jennifer H Kong ◽  
Sigrid Nachtergaele ◽  
Andreas Sagner ◽  
...  
Keyword(s):  
Structural Analysis ◽  
G Protein ◽  
Hedgehog Signaling ◽  
Cell Communication ◽  
G Protein Coupled Receptors ◽  
Rich Domain ◽  
Hh Signaling ◽  
G Protein Coupled ◽  
Orphan Gpcr ◽  
Cysteine Rich Domain

Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike many GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.

scholarly journals Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling

2016 ◽  
Author(s):  
Giovanni Luchetti ◽  
Ria Sircar ◽  
Jennifer H. Kong ◽  
Sigrid Nachtergaele ◽  
Andreas Sagner ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Cell Surface ◽  
G Protein ◽  
Cell Communication ◽  
G Protein Coupled Receptors ◽  
Rich Domain ◽  
Hh Signaling ◽  
G Protein Coupled ◽  
Orphan Gpcr ◽  
Cysteine Rich Domain

AbstractCholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike most GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald Levy ◽  
Yinglong Miao
Keyword(s):  
Structural Analysis ◽  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs. Functional mechanisms of GPCRs remain poorly understood. Here, we have constructed sequence coevolutionary models of the A, B and C classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts have been successfully detected in the sequence-based covariational models. "Exception" residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Our combined coevolutionary and structural analysis revealed unique features of the different classes of GPCRs. First, we provided evidence from coevolutionary couplings that dimerization is required for activation of class C GPCRs, but not for activation of class A and B GPCRs. Second, we identified distinct residue contacts involving different sets of functional motifs for activation of the class A and B GPCRs. Finally, we uncovered critical residue contacts tuned by allosteric modulation in the three classes of GPCRs. These findings provide a promising framework for designing selective therapeutics of GPCRs.

scholarly journals Abstract P-6: G-Protein Coupled Receptors Engineering for Structural Analysis

2019 ◽  
Vol 9 (Suppl_1) ◽  
pp. S19-S19
Author(s):  
Aleksandra Luginina ◽  
Anastasiia Gusach ◽  
Valentin Borshchevskiy ◽  
Alexey Mishin
Keyword(s):  
Structural Analysis ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Acute loss of Cell–Cell Communication Caused by G Protein–coupled Receptors: A Critical Role for c-Src

1998 ◽  
Vol 140 (5) ◽  
pp. 1199-1209 ◽  
Author(s):  
Friso R. Postma ◽  
Trudi Hengeveld ◽  
Jacqueline Alblas ◽  
Ben N.G. Giepmans ◽  
Gerben C.M. Zondag ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Gap Junction ◽  
G Protein ◽  
Critical Role ◽  
Cell Communication ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled Receptor ◽  
Junction Protein ◽  
G Protein Coupled ◽  
Cell Cell

Gap junctions mediate cell–cell communication in almost all tissues, but little is known about their regulation by physiological stimuli. Using a novel single-electrode technique, together with dye coupling studies, we show that in cells expressing gap junction protein connexin43, cell–cell communication is rapidly disrupted by G protein–coupled receptor agonists, notably lysophosphatidic acid, thrombin, and neuropeptides. In the continuous presence of agonist, junctional communication fully recovers within 1–2 h of receptor stimulation. In contrast, a desensitization-defective G protein–coupled receptor mediates prolonged uncoupling, indicating that recovery of communication is controlled, at least in part, by receptor desensitization. Agonist-induced gap junction closure consistently follows inositol lipid breakdown and membrane depolarization and coincides with Rho-mediated cytoskeletal remodeling. However, we find that gap junction closure is independent of Ca2+, protein kinase C, mitogen-activated protein kinase, or membrane potential, and requires neither Rho nor Ras activation. Gap junction closure is prevented by tyrphostins, by dominant-negative c-Src, and in Src-deficient cells. Thus, G protein–coupled receptors use a Src tyrosine kinase pathway to transiently inhibit connexin43-based cell–cell communication.

scholarly journals G Protein-Coupled Receptors: Dominant Players in Cell–Cell Communication

2002 ◽  
pp. 63-136e ◽  
Author(s):  
Joël Bockaert ◽  
Sylvie Claeysen ◽  
Carine Bécamel ◽  
Pinloche Sylvie ◽  
Aline Dumuis
Keyword(s):  
G Protein ◽  
Cell Communication ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled ◽  
Cell Cell

scholarly journals Lysine63-linked ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia

2020 ◽  
Author(s):  
Swapnil Rohidas Shinde ◽  
Andrew R. Nager ◽  
Maxence V. Nachury
Keyword(s):  
G Protein ◽  
Somatostatin Receptor ◽  
G Protein Coupled Receptors ◽  
Dependent Manner ◽  
Bardet Biedl Syndrome ◽  
Ubiquitinated Proteins ◽  
Molecular Sensor ◽  
Regulated Trafficking ◽  
G Protein Coupled ◽  
Orphan Gpcr

ABSTRACTRegulated trafficking of G-protein coupled receptors (GPCRs) controls cilium-based signaling pathways. β-arrestin, a molecular sensor of activated GPCRs, and the BBSome, a complex of Bardet-Biedl Syndrome (BBS) proteins, are required for the signal-dependent exit of ciliary GPCRs but the functional interplay between β-arrestin and the BBSome remains elusive. Here we find that, upon activation, ciliary GPCRs become tagged with K63-linked ubiquitin (K63Ub) chains in a β-arrestin-dependent manner prior to BBSome-mediated exit. Removal of ubiquitin acceptor residues from the somatostatin receptor 3 (SSTR3) and from the orphan GPCR GPR161 demonstrates that ubiquitination of ciliary GPCRs is required for their regulated exit from cilia. Furthermore, targeting a K63Ub-specific deubiquitinase to cilia blocks the exit of GPR161, SSTR3 and Smoothened (SMO) from cilia. Finally, ubiquitinated proteins accumulate in cilia of mammalian photoreceptors and Chlamydomonas cells when BBSome function is compromised. We conclude that K63Ub chains mark GPCRs and other unwanted ciliary proteins for recognition by the ciliary exit machinery.

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