Contribution of heteromerization to G protein-coupled receptor function

Gaitonde, Supriya A; González-Maeso, Javier

doi:10.1016/j.coph.2016.10.006

Cited by 55 publications

(36 citation statements)

References 90 publications

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“…Studies have also suggested the signal from GPCR may differ when costimulated with a neighboring GPCR . Therefore, our scaffold has good potential to display GPCR ligands in specific patterns to study the arrangement of GPCR complexes on membranes as well as the effects of GPCR costimulation, which are otherwise difficult to investigate through current available tools. In addition, compared to ligand patch patterns on glass slides or other surfaces created from top‐down approaches, our scaffold provides promising therapeutic potentials to manipulate cell surface receptors or target secreted lectins as the PP3M scaffold is water soluble and biocompatible.…”

Section: Resultsmentioning

confidence: 99%

Polyproline Tri‐Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions

Lin

Wen

Chiang

et al. 2019

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cells circulation are governed. [2] While many binding events take place within lipid microdomains on cell membranes, receptors can assemble into multireceptor complexes and exchange information directly through protein contact. [3] As the combination of these receptors can lead to alternative outcome in the signaling process, in addition to traditional studies based on monomeric receptor, multiple neighboring receptors would preferably be concurrently investigated at their native oligomeric state on the intact cell membrane for a better understanding. To this end, knowing how the receptors arrange on the plasma membrane is essential not only to reveal how their combination leads to functions but also to help synthetic chemists to create customized molecules to manipulate such processes. The asialoglycoprotein receptor (ASGPR), a galactose/ GalNAc-binding hepatic protein employed for drug delivery to hepatocytes, represents an example to address this issue as it forms oligomers by the combinations of two receptor subtypes. [4] Without detailed oligomeric structure, the distances between three ligand-binding sites of ASGPR trimer were estimated at 15, 20, and 25 Å by the glycan-binding studies. [5] A strategy to precisely control the patterns of multiple ligands [6] would aid in probing the ASGPR arrangement correlated to its function and manipulating the selectivity for the drug delivery. Toward this goal, a promising, yet challenging, approach is to develop an artificial molecular platform to control ligand patterns (Figure 1a).Ligand patterning is also an important factor for carbohydrate-lectin binding, which usually involves multiple simultaneous binding events to enhance the overall strength and allow for recognition. The concept of multivalent binding pioneered by Lee [7] and continued by others with thermodynamics explanations [8] has initiated the development of scaffolds supporting multiple glycan ligands to elicit strong interaction with proteins. [9] Glycoliposomes/micelles, [10] glycodendrimers, [11] glycopolymers, [12] and glycoclusters (including glycocyclopeptides) [9c,13] are among popular glycoconjugates that significantly enhanced binding avidity. However, protein-carbohydrate interaction is usually accompanied by cross-reactivity allowing a glycan ligand to interact with different Multivalent ligand-receptor interactions play essential roles in biological recognition and signaling. As the receptor arrangement on the cell surface can alter the outcome of cell signaling and also provide spatial specificity for ligand binding, controlling the presentation of ligands has become a promising strategy to manipulate or selectively target protein receptors. The lack of adjustable universal tools to control ligand positions at the size of a few nanometers has prompted the development of polyproline tri-helix macrocycles as scaffolds to present ligands in designated patterns. Model lectin Helix pomatia agglutinin has shown selectivity toward the matching GalNAc ligand pattern matching its binding sit...

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Section: Resultsmentioning

confidence: 99%

Polyproline Tri‐Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions

Lin

Wen

Chiang

et al. 2019

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“…With more than 900 members encoded in the human genome, the seven-transmembrane domain (TMD) G protein-coupled receptors (GPCRs) represent the largest family of membrane proteins and are the targets of many therapeutic drugs. In recent years, several lines of evidence have revealed the formation of physiologically active oligomers of GPCRs [1,2]. The initial discovery of the obligatory heterodimeric structure of the γ-aminobutyric acid B, GABA B1 -GABA B2, receptor was triggered through various observations, including (i) the co-localization of mRNA for both receptor subtypes in any cell with a metabotropic GABA B receptor response and co-immunoprecipitation studies in brain tissue, and (ii) the requirement for co-transfection of cells with GABA B1 -and GABA B2-encoding DNA constructs to produce a functional GABA B receptor expressed on the plasma membrane and able to recognize its ligand [3].…”

Section: Introductionmentioning

confidence: 99%

“…forming units of oligomers). In family C GPCRs, the metabotropic glutamate (mGlu) receptors have also been shown to exist as covalently-linked obligatory dimers [1].…”

Section: Introductionmentioning

confidence: 99%

Dimers of serotonin receptors: Impact on ligand affinity and signaling

2019

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Membrane receptors often form complexes with other membrane proteins that directly interact with different effectors of the signal transduction machinery. G-protein-coupled receptors (GPCRs) were for long time considered as single pharmacological entities. However, evidence for oligomerization appeared for various classes and subtypes of GPCRs. This review focuses on metabotropic serotonin (5-hydroxytryptamine, 5-HT) receptors, which belong to the rhodopsin-like class A of GPCRs, and will summarize the convergent evidence that homo-and hetero-dimers containing 5-HT receptors exist in transfected cells and in-vivo. We will show that complexes involving 5-HT receptors may acquire new signal transduction pathways and new physiological roles. In some cases, these complexes participate in disease-specific deregulations, that can be differentially affected by various drugs. Hence, selecting receptor complex-specific responses of these heterodimers may constitute an emerging strategy likely to improve beneficial therapeutic effects.

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“…In the context of this review, cholesterol is gaining increasing relevance in GPCR function as a possible modulator of GPCR oligomerization. A matter of debate for more than a decade, it is now more widely accepted that various types of GPCRs undergo dimerization or higher-order oligomerization prior to activation [5], and although monomers in family type A GPCRs are functional, heteromerization appears to be fundamental in receptor trafficking and pharmacology [55]. Current views strongly point to the membrane microenvironment as the key modulator of GPCR oligomerization [54] and more specifically to cholesterol as the dimerization-inducing membrane component [54,104].…”

Section: Fj Barrantes / Cholesterol-receptor Interactionsmentioning

confidence: 99%

“…GPCRs constitute the largest superfamily of transmembrane proteins, with more than 900 members encoded by the human genome [55]. Their biomedical and economic importance is outlined by the fact S76…”

Section: Cholesterol Effects On the Oligomeric State Of G-protein-coumentioning

confidence: 99%

Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

Barrantes

2016

BSI

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Abstract. Once the sterol biosynthetic machinery had progressed over the course of several million years to yield cholesterol, this neutral lipid became an omnipresent and essential component of biomembranes in Eukaryotes. The hopanoids in Prokaryotes and eukaryotic sterols share the ability to provide stability and domain compartmentalization in membranes. Even more important is the intimate association of cholesterol with a wide range of cell-surface membrane proteins, probably responsible for its modulatory effects on neurotransmitter and hormone receptors and ion channels. These effects appear to be exerted via the membrane-embedded segments of essentially all members of the pentameric ligand-gated ion channel and G-protein-coupled receptor superfamilies, which possess consensus linear arrays of amino acid residues recognizing cholesterol with relatively high affinity and specificity, an early evolutionary acquisition already present in ancient bacteria, conserved, and further improved in Eukaryotes. This review focuses on the long-term relationship between cholesterol and these functionally important membrane protein superfamilies, and the ability of cholesterol to induce lateral segregation and ordered domain formation at the nanoscale in cell membranes.

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Contribution of heteromerization to G protein-coupled receptor function

Cited by 55 publications

References 90 publications

Polyproline Tri‐Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions

Polyproline Tri‐Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions

Dimers of serotonin receptors: Impact on ligand affinity and signaling

Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

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