Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism

Castro, Marián; Nikolaev, Viacheslav O.; Palm, D.; Lohse, Martin J.; Vilardaga, Jean-Pierre

doi:10.1073/pnas.0503942102

Cited by 169 publications

(162 citation statements)

References 29 publications

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“…The CRF ligand-receptor system is a prototype for peptide hormone GPCRs. The modular behavior of the CRF receptors with the ECD1 as the major peptide binding domain is also reported for other members of the peptide hormone GPCR family such as parathyroid hormone (12,40,41,43,44) and the SCR motif of the ECD1 is predicted to be conserved in all of the ECD1s of the B1 family of GPCRs (18). The modular property is also present for various peptide hormones such as parathyroid hormone (45).…”

Section: Crf Ligand-receptor Interactions Have a Common Binding Modementioning

confidence: 83%

Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand

Grace¹,

Perrin

Gulyás

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

126

175

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The corticotropin releasing factor (CRF) family of ligands and their receptors coordinate endocrine, behavioral, autonomic, and metabolic responses to stress and play additional roles within the cardiovascular, gastrointestinal, and other systems. The actions of CRF and the related urocortins are mediated by activation of two receptors, CRF-R1 and CRF-R2, belonging to the B1 family of G protein-coupled receptors. The short-consensus-repeat fold (SCR) within the first extracellular domain (ECD1) of the CRF receptor(s) comprises the major ligand binding site and serves to dock a peptide ligand via its C-terminal segment, thus positioning the N-terminal segment to interact with the receptor's juxtamembrane domains to activate the receptor. Here we present the 3D NMR structure of ECD1 of CRF-R2␤ in complex with astressin, a peptide antagonist. In the structure of the complex the C-terminal segment of astressin forms an amphipathic helix, whose entire hydrophobic face interacts with the short-consensus-repeat motif, covering a large intermolecular interface. In addition, the complex is characterized by intermolecular hydrogen bonds and a salt bridge. These interactions are quantitatively weighted by an analysis of the effects on the full-length receptor affinities using an Ala scan of CRF. These structural studies identify the major determinants for CRF ligand specificity and selectivity and support a two-step model for receptor activation. Furthermore, because of a proposed conservation of the fold for both the ECD1s and ligands, this structure can serve as a model for ligand recognition for the entire B1 receptor family.3D structure ͉ astressin ͉ corticotropin releasing factor ͉ NMR T he ability of the body to adapt to stressful stimuli and the role of stress maladaptation in human diseases has been intensively investigated. Corticotropin releasing factor (CRF) (1), a 41-residue peptide, and its three paralogous peptides, urocortin (Ucn) 1, 2, and 3, play important and diverse roles in coordinating endocrine, autonomic, metabolic, and behavioral responses to stress (2, 3). CRF family peptides and their receptors are also implicated in the modulation of additional central nervous system functions including appetite, addiction, hearing, and neurogenesis and act peripherally within the endocrine, cardiovascular, reproductive, gastrointestinal, and immune systems (4, 5). CRF and related ligands initially act by binding to their G protein-coupled receptors (GPCRs). These belong to the peptide hormone B1 family (family B1 GPCRs), comprising receptors for growth hormone releasing factor, secretin, calcitonin, vasoactive intestinal peptide, glucagon, glucagon-like peptide-1, and parathyroid hormone. Two CRF receptors, CRF-R1 and CRF-R2, have been cloned in mammals (6, 7).Structure activity studies of CRF showed that the first eight N-terminal residues of the hormone are necessary for GPCR signaling (1, 8), whereas the C-terminal (Ϸ15) residues are important for binding (9,10). A two-domain behavior for ligand binding was a...

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Section: Crf Ligand-receptor Interactions Have a Common Binding Modementioning

confidence: 83%

Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand

Grace¹,

Perrin

Gulyás

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

126

175

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“…We therefore tested whether stabilizing arrestin association with PTHR would also permit its interaction with Gβγ. To do this, we artificially immobilized an N-terminally GFP-tagged PTHR (PTHR-GFP) (22) at the plasma membrane of HEK293 cells and used a mutant of β-arrestin 1, I 386 A, V 387 A (hereafter β-arr1[IV-AA], or β-arr1[IV-AA] Tom when tagged with tdTomato), that exhibits increased binding affinity for ligand-activated PTHR (14). Cell-surface cross-linking effectively immobilized PTHR without affecting its signaling capacity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

Wehbi

Stevenson

Feinstein³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

159

107

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G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G S )-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G S activation and increases the steady-state levels of activated G S , leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.

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“…The NTDs of family B GPCRs share a common fold stabilized by three disulfides, and contribute most of the binding affinity of the receptor for the peptide 4, 5 . A two-step, two-domain model of activation has been proposed where the C-terminus of the agonist peptide initially engages the NTD 6 . After this initial binding event, the N-terminal end of the peptide engages and activates the 7TMD with a mechanism that is currently unknown.…”

mentioning

confidence: 99%

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Zhang

Sun

Feng

et al. 2017

Nature

503

568

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Summary Glucagon-like peptide-1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to GLP-1R, a family B G protein-coupled receptor (GPCR) signaling primarily through the stimulatory G protein Gs. Family B GPCRs are important therapeutic targets, however our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we show the electron cryo-microscopy structure of the peptide-activated GLP-1R:Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and transmembrane core of the receptor, further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5 helix of GαsRas. These results provide a structural framework for understanding family B receptor activation through hormone binding.

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Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism

Cited by 169 publications

References 29 publications

Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand

Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand

Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

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