Allosteric Activation of a Spring-Loaded Natriuretic Peptide Receptor Dimer by Hormone

He, Xiaolin; Chow, Dar‐Chone; Martick, Monika; García, K. Christopher

doi:10.1126/science.1062246

Cited by 159 publications

(181 citation statements)

References 43 publications

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“…Receptor conformational change, especially rearrangements involving interdomain movements (12,25,26), is now gaining recognition as an important mechanism for controlling ligand binding. Thus, bulky amino acid side chain (12) and glycan wedges may have broad applications in designing mutant receptors with modified affinity.…”

Section: Discussionmentioning

confidence: 99%

Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand

Luo

Springer

Takagi

2003

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

146

186

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The affinity of the extracellular domain of integrins for ligand is regulated by conformational changes signaled from the cytoplasm. Alternative types of conformational movement in the ligandbinding headpiece have been proposed. In one study, electron micrograph image averages of the headpiece of integrin aV␤3 show two different conformations. The open conformation of the headpiece is present when a ligand mimetic peptide is bound and differs from the closed conformation in the presence of an obtuse angle between the ␤3 subunit hybrid and I-like domains. We tested the hypothesis that opening of the hybrid-I-like domain interface increases ligand-binding affinity by mutationally introducing an N-glycosylation site into it. Both ␤3 and ␤1 integrin glycan wedge mutants exhibit constitutively high affinity for physiological ligands. The data uniquely support one model of integrin activation and suggest that movement at the interface with the hybrid domain pulls down the C-terminal helix of the I-like domain and activates its metal ion-dependent adhesion site, analogously to activation of the integrin I domain.I ntegrins are a family of Ϸ25 cell adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions and govern migration and anchorage of almost all kinds of cells. Integrins are noncovalently associated ␣␤ subunit heterodimers. Each subunit contains a large N-terminal extracellular domain, a transmembrane segment, and a cytoplasmic C-terminal tail. One unique aspect of integrin function is that the affinity for biological ligand can be up-regulated by a process termed inside-out signaling (1). This is particularly important during activation of leukocytes and platelets, where integrins are converted to high-affinity receptors in Ͻ1 s. It has been suggested that this rapid affinity up-regulation is accomplished by a conformational change in integrin extracellular domains triggered by cytoplasmic signaling pathways after cellular activation.Several alternative models for conformational change have been proposed. Crystal structures obtained of the extracellular domain of ␣V␤3 in Ca 2ϩ (2) or by subsequent soaking in Mn 2ϩ and a cyclic Arg-Gly-Asp (RGD) peptide (3) revealed an unexpected bent conformation, in which the headpiece is folded over and makes extensive contacts with the tailpiece (Fig. 1A). Upon ligand binding, no change was seen at the interface between the I-like and hybrid domains, and only a slight rotation between the ␤-propeller and I-like domains and small movements within the I-like domain were seen. It was hypothesized that both the liganded and unliganded bent structures were in the active state (2, 3). In contrast, NMR, negative stain electron microscopy (EM) with image averaging, ligand binding, physicochemical, and mutational studies show that the bent conformation is physiologic and has low ligand-binding affinity and that activation results in a switchblade-like opening to an extended conformation (4, 5). Two extended conformers were seen that differed...

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Section: Discussionmentioning

confidence: 99%

Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand

Luo

Springer

Takagi

2003

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

146

186

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“…X-ray structures have been solved for the extracellular domains of mGluR type 1 (mGlu1) (Kunishima et al, 2000;Tsuchiya et al, 2002) and ANP receptor (ANPR) types A and C (He et al, 2001;van den Akker, 2001) produced as soluble proteins. These domains are bilobate proteins often called Venus flytrap modules (VFTMs) and share similar sequence homology with the extracellular domain of the GABA B subunits (Fig.…”

Section: Introductionmentioning

confidence: 99%

Locking the Dimeric GABA_BG-Protein-Coupled Receptor in Its Active State

Kniazeff¹,

Saintot²,

Goudet³

et al. 2004

J. Neurosci.

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G-protein-coupled receptors (GPCRs) play a major role in cell-cell communication in the CNS. These proteins oscillate between various inactive and active conformations, the latter being stabilized by agonists. Although mutations can lead to constitutive activity, most of these destabilize inactive conformations, and none lock the receptor in an active state. Moreover, GPCRs are known to form dimers, but the role of each protomer in the activation process remains unclear. Here, we show that the heterodimeric GPCR for the main inhibitory neurotransmitter, the GABA B receptor, can be locked in its active state by introducing two cysteines expected to form a disulphide bridge to maintain the binding domain of the GABA B1 subunit in a closed form. This constitutively active receptor cannot be inhibited by antagonists, but its normal functioning, activation by agonists, and inhibition by antagonists can be restored after reduction with dithiothreitol. These data show that the closed state of the binding domain of GABA B1 is sufficient to turn ON this heterodimeric receptor and illustrate for the first time that a GPCR can be locked in an active conformation.

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“…CNP is a potent relaxant of vascular smooth muscle, particularly in the coronary circulation (14,15), and also inhibits smooth muscle cell proliferation (16) and aldosterone production (17,18). The cardiovascular actions of CNP are mediated via activation of the NPR subtypes, NPR-B (for which it is the preferential ligand) and NPR-C (19), the latter accounting for Ϸ95% of NPRs expressed in vivo (20). Moreover, recent evidence suggests that the mechanism by which CNP mediates vasorelaxation (including human vessels) is via an NPR-mediated hyperpolarization of vascular smooth muscle, because responses are sensitive to blockade by tetraethylammonium (21).…”

mentioning

confidence: 99%

Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor

Chauhan

Nilsson

Ahluwalia

et al. 2003

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

210

209

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Endothelial cells in most vascular beds release a factor that hyperpolarizes the underlying smooth muscle, produces vasodilatation, and plays a fundamental role in the regulation of local blood flow and systemic blood pressure. The identity of this endotheliumderived hyperpolarizing factor (EDHF), which is neither NO nor prostacyclin, remains obscure. Herein, we demonstrate that in mesenteric resistance arteries, release of C-type natriuretic peptide (

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Allosteric Activation of a Spring-Loaded Natriuretic Peptide Receptor Dimer by Hormone

Cited by 159 publications

References 43 publications

Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand

Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand

Locking the Dimeric GABA_BG-Protein-Coupled Receptor in Its Active State

Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor

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Allosteric Activation of a Spring-Loaded Natriuretic Peptide Receptor Dimer by Hormone

Cited by 159 publications

References 43 publications

Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand

Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand

Locking the Dimeric GABABG-Protein-Coupled Receptor in Its Active State

Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor

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Locking the Dimeric GABA_BG-Protein-Coupled Receptor in Its Active State