Molecular basis for activation of G protein-coupled receptor kinases

Boguth, Cassandra A.; Singh, Puja; Huang, Can; Tesmer, John J.G.

doi:10.1038/emboj.2010.206

Cited by 91 publications

(190 citation statements)

References 44 publications

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“…Interestingly, some common interaction partners of GPCRs, such as GPCR kinases (GRK), have the possibility to couple to disordered regions of the receptor comprising ICL3 and the C-terminal tail (Boguth et al, 2010;Elgeti et al, 2013). The presence of these highly flexible linkers also facilitates conformational changes allowing large movements of the TM domains (Rasmussen et al, 2011), making possible a diversity of TM interactions.…”

Section: Structural Biology Of Receptor Complexesmentioning

confidence: 99%

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%

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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“…Modeling based on EPR restraints suggests a propensity for the finger loop to form a helix in both free and bound states. Interestingly, members of three protein families that preferentially bind active GPCRs, namely G proteins (54,55), G protein-coupled receptor kinases (56)(57)(58), and arrestins (14), all have flexible sequences that transition to a helical conformation when bound to GPCRs. In each case, the helical segment is proposed to bind in or near the central cavity of the activated receptor.…”

mentioning

confidence: 99%

Conformation of receptor-bound visual arrestin

Kim

Vishnivetskiy²,

Eps

et al. 2012

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

105

172

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Arrestin-1 (visual arrestin) binds to light-activated phosphorylated rhodopsin (P-Rh*) to terminate G-protein signaling. To map conformational changes upon binding to the receptor, pairs of spin labels were introduced in arrestin-1 and double electron-electron resonance was used to monitor interspin distance changes upon P-Rh* binding. The results indicate that the relative position of the N and C domains remains largely unchanged, contrary to expectations of a "clam-shell" model. A loop implicated in P-Rh* binding that connects β-strands V and VI (the "finger loop," residues 67-79) moves toward the expected location of P-Rh* in the complex, but does not assume a fully extended conformation. A striking and unexpected movement of a loop containing residue 139 away from the adjacent finger loop is observed, which appears to facilitate P-Rh* binding. This change is accompanied by smaller movements of distal loops containing residues 157 and 344 at the tips of the N and C domains, which correspond to "plastic" regions of arrestin-1 that have distinct conformations in monomers of the crystal tetramer. Remarkably, the loops containing residues 139, 157, and 344 appear to have high flexibility in both free arrestin-1 and the P-Rh*complex.A rrestin was first discovered in the visual system as a protein that blocks ("arrests") the signaling of the prototypical G protein-coupled receptor (GPCR) rhodopsin (Rh) via specific binding to the phosphorylated activated form P-Rh* (1). Mammals express four arrestin subtypes: Arrestin-1 and -4 are specific for the visual system, whereas arrestin-2 and -3 are ubiquitous (2). [We use systematic names of arrestins: arrestin-1 (historic names S-antigen, 48-kDa protein, or visual or rod arrestin), arrestin-2 (β-arrestin or β-arrestin1), arrestin-3 (β-arrestin2 or hTHY-ARRX), and arrestin-4 (cone or X-arrestin).] The discovery of nonvisual arrestins (3) showed that phosphorylation followed by arrestin binding is a common mechanism of GPCR regulation. Crystal structures of all four arrestin subtypes in their basal state revealed similar topology: two cup-like domains linked by an interdomain hinge ( Fig. 1) (4-7). Arrestin-1 was proposed to undergo a conformational rearrangement during the P-Rh* interaction that results in the release of the C-terminal sequence (C tail) (8, 9) but does not involve major secondary structure changes (8, 10). Recent site-directed spin labeling (SDSL) studies identified specific parts of arrestin-1 engaged by different functional forms of rhodopsin and provided direct evidence of binding-induced conformational changes (11,12). A conformational change in the so-called finger loop (Fig. 1) implicated in P-Rh* recognition was also observed using NMR and fluorescence quenching (13,14). Arrestin-1 shows a remarkable selectivity for P-Rh*. Observed binding to inactive phosphorylated (P-Rh) or active unphosphorylated rhodopsin (Rh*) is usually less than 10% of the binding to P-Rh*, whereas its binding to inactive unphosphorylated rhodopsin (Rh) is barely detectable ...

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“…This is in strict contrast to GRK6 (70.4% sequence identity to GRK5), which adopts distinct conformations in the presence of AMP-PNP (28) and sangivamycin (r.m.s.d. 1.94 Å) (30). The observed difference between GRK5 and GRK6 is likely dictated by structural restraints imposed by crystal contacts, which appeared to be ligand-independent in …”

Section: Resultsmentioning

confidence: 99%

“…GRK5 Is a Monomer Both in the Crystal Structure and in Solution-GRK1 and GRK6 crystallized as dimers in the asymmetric unit with the C termini of each molecule mediating a domain-swapped dimer interface (24,28,30). In contrast, GRK5 is a monomer in the crystal structure.…”

Section: Pdb Code 4tnd 4tnbmentioning

confidence: 95%

“…Several studies suggest that an N-terminal ␣-helical domain plays an important role in regulating catalytic domain closure via a process that is likely regulated by receptor binding (29 -31). Indeed, this domain has been observed in one crystal form of GRK1 (24,31) as well as in GRK6 in complex with either sangivamycin or AMP (30) and appears to stabilize catalytic domain closure. Although crystallography has provided significant insight on GRK1, -2, and -6, there have been no studies to date on the structural analysis of GRK5.…”

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confidence: 99%

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Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases

Komolov

Bhardwaj

Benovic

2015

Journal of Biological Chemistry

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Background: GRK5 is implicated in several human pathologies, but relatively little is known about its structure and function. Results: High resolution crystal structures of human GRK5 with AMP-PNP and sangivamycin were determined. Conclusion: GRK5 is found in a partially closed state with its kinase domain C-tail forming novel interactions with nucleotide and the N-lobe. Significance: The GRK5 structure provides important insight into its function.

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Molecular basis for activation of G protein-coupled receptor kinases

Cited by 91 publications

References 44 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

Conformation of receptor-bound visual arrestin

Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases

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