Structural plasticity in G-protein coupled receptors as demonstrated by the allosteric actions of homocysteine and computer-assisted analysis of disordered domains

Agnati, Luigi F.; Leo, Giuseppina; Genedani, Susanna; Andreoli, Nicola; Marcellino, Daniel; Woods, Amina S.; Piron, Lamberto; Guidolin, Diego; Fuxé, Kjell

doi:10.1016/j.brainresrev.2007.10.003

Cited by 40 publications

(50 citation statements)

References 47 publications

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“…As shown by crystallographic studies, the overall structure of GPCR proteins is highly conserved, but significant diversities can be observed in the loop regions and in the pitch and orientation of individual TM in the helical bundle (Lu and Wu, 2016). Such a quite high plasticity of the GPCR structure is likely a consequence of the presence of intrinsically disordered segments that do not fold into a stable secondary structure (Agnati et al, 2008;Venkatakrishnan et al, 2014). Computational and structural studies have revealed that GPCRs harbor disordered segments in the extracellular N-terminus and large disordered areas in the cytosolic region, mainly in the intracellular C-terminus and in the ICLs, particularly ICL3 (Agnati et al, 2008;Guidolin et al, 2011a;Venkatakrishnan et al, 2014).…”

Section: Structural Biology Of Receptor Complexesmentioning

confidence: 99%

“…Such a quite high plasticity of the GPCR structure is likely a consequence of the presence of intrinsically disordered segments that do not fold into a stable secondary structure (Agnati et al, 2008;Venkatakrishnan et al, 2014). Computational and structural studies have revealed that GPCRs harbor disordered segments in the extracellular N-terminus and large disordered areas in the cytosolic region, mainly in the intracellular C-terminus and in the ICLs, particularly ICL3 (Agnati et al, 2008;Guidolin et al, 2011a;Venkatakrishnan et al, 2014). These results have been recently supported by Tovo-Rodrigues et al (2014) who provided a detailed analysis of disordered domains in 75 GPCRs involved in synaptic transmission using computational tools for the sequence-based prediction of intrinsically disordered regions within a protein.…”

Section: Structural Biology Of Receptor Complexesmentioning

confidence: 99%

“…Thus, ligands could also exist specific to the receptor complex as such (see Fuxe et al, 2010). Studies on the effect of homocysteine (Agnati et al, 2006(Agnati et al, , 2008 …”

Section: Quaternary Structure Of Gpcr Complexesmentioning

confidence: 99%

“…In fact, in the presence of the H 3 receptor, D 1 receptors were no longer coupled to G s and could not activate adenylyl cyclase but were coupled to G i , which Receptor complexes appear to be endowed with characteristics and functions that could not be fully derived from the characteristics of the single participating receptor monomers. When the complex forms, for instance, the quaternary structure could display novel specific allosteric sites (Agnati et al, 2008). Furthermore, RM are in the center of two complementary networks of interactions: HMN involving (A) the lipid environment (Gahbauer and Böckmann, 2016), (B) RAMP (Foord and Marshall, 1999), (C) RTK , and (D) membrane channels (Liu et al, 2006a;Gamo et al, 2015) and VMN leading to (E) modulation of the binding sites (Fuxe et al, 1998), (F) modulation of G protein activation (Ferrada et al, 2009), (G) modulation of the signaling cascade, among others, and (H) switching from G protein to β-arrestin signaling (Rashid et al, 2007;Rozenfeld et al, 2012).…”

Section: Rm and Vmnsmentioning

confidence: 99%

“…Using sequence features, for instance, several methods have been developed to classify whether any given residue belongs to protein segments potentially relevant for protein-protein interaction, such as intrinsically disordered regions (Ferron et al, 2006). Agnati et al (2008) introduced a 'disorder index' as the weighted average of the results provided by 10 predictors, covering a wide spectrum of the strategies to identify disordered regions in proteins using their primary structure. The results suggested ICL3 and C-terminal domains as potential sites of interaction interfaces for A 1 and A 2A adenosine receptors, whereas, in A 2B and A 3 subtypes, only the C-terminal domain exhibited a significant score.…”

Section: Interaction Interfacesmentioning

confidence: 99%

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G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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Abstract:The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

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Section: Structural Biology Of Receptor Complexesmentioning

confidence: 99%

Section: Structural Biology Of Receptor Complexesmentioning

confidence: 99%

“…Thus, ligands could also exist specific to the receptor complex as such (see Fuxe et al, 2010). Studies on the effect of homocysteine (Agnati et al, 2006(Agnati et al, , 2008 …”

Section: Quaternary Structure Of Gpcr Complexesmentioning

confidence: 99%

Section: Rm and Vmnsmentioning

confidence: 99%

Section: Interaction Interfacesmentioning

confidence: 99%

See 3 more Smart Citations

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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Moonlighting characteristics of G protein‐coupled receptors: Focus on receptor heteromers and relevance for neurodegeneration

et al. 2011

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SummaryIt is proposed that the moonlighting concept can be applied to G protein coupled receptors (GPCRs) as, obviously, they can carry out different types of functions. The same motifs in, for example, the third intracellular loop, can moonlight by switching between receptor-receptor interactions and interactions with signaling proteins such as G proteins or calmodulin. A ''guide-and-clasp'' manner of receptor-receptor interactions has been proposed where the ''adhesive guides'' may be the triplet homologies. As an example, the triplets AAR (or RAA) and AAE (or EAA) homologies in A 2A R-D 2 R heteromers may guideand-clasp binding not only of the two protomers but also of calmodulin and G i . A beautiful moonlighting phenomenon in the A 2A R-D 2 R heteromer is that the positively charged D 2 R N-terminal third intracellular loop epitope (VLRRRRKRVN) may switch between bindings to the negatively charged A 2A R epitope (SAQEpSQGNT), localized in the medium segment of the C terminus of the A2A receptor to several negative epitopes of calmodulin. Furthermore, overlapping motifs may favor moonlighting to G i/o via inter alia electrostatic interaction between triplets AAR(in D 2 R third intracellular loop) and AAE (G i/alpha1 ) (and/or their symmetric variants) contributing to guide-and-clasp D 2 R-G i interactions Thus, moonlighting in GPCR heteromers can take place via allosteric receptor-receptor interactions and is also described in D 1 R-D 2 R, D 2 R-5-HT 2 R,and A 1 R-P2Y1 heteromers. Allosteric receptor-receptor interactions in GPCR-receptor tyrosine kinases (RTKs) heteromers and postulated ion channel receptor-RTK heteromers-like, for example, AMPA-NMDA-TrkB heteromers may lead to moonlighting of the participating GPCR and RTK protomers altering, for example, the pattern of the five major signaling pathways of the RTKs favoring MAPK and/or mTOR signaling with high relevance for neurodegenerative processes and depression induced atrophy of neurons. Moonlighting may also develop in the intracellular loops and C-terminal of the GPCRs as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptor.

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Dopamine Receptor Oligomerization

Fuxé

Marcellino

Guidolin

et al. 2009

The Dopamine Receptors

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Structural plasticity in G-protein coupled receptors as demonstrated by the allosteric actions of homocysteine and computer-assisted analysis of disordered domains

Cited by 40 publications

References 47 publications

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Moonlighting characteristics of G protein‐coupled receptors: Focus on receptor heteromers and relevance for neurodegeneration

Dopamine Receptor Oligomerization

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