A complex structure of arrestin-2 bound to a G protein-coupled receptor

Yin, Wanchao; Li, Z.; Jin, Mingliang; Yin, Yuanyuan; Waal, Parker W. de; Pal, Kuntal; Gao, Xiang; He, Yao; Gao, Jing; Wang, X.; Zhang, Yan; Zhou, Hu; Melcher, Karsten; Jiang, Yi; Yao, Cong; Zhou, Xuemei; Yu, Xuekui; Xu, Hao

doi:10.1038/s41422-019-0256-2

Cited by 176 publications

(269 citation statements)

References 46 publications

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“…Nevertheless, it is tempting to hypothesize that other residue combinations bias arrestin-mediated signaling in this system towards different effectors (7,8). This is consistent with reported different shapes of the arrestin-receptor complex (68)(69)(70). We also identified different effects of G protein on this process, with Gs enhancing ERK1/2 but not Src activation.…”

Section: Discussionsupporting

confidence: 87%

“…Crystal structures of the receptor-arrestin complexes indeed reveal that arrestin binds to both the phosphorylated elements in the C-terminus and the pocket unique to active receptor (the main G protein binding site) (67)(68)(69)(70). While phosphorylation commonly reduces G protein coupling (71)(72)(73), in some cases it changes the G protein subtype that couples to receptor (50,74).…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

Kaya

Perry

Gurevich

et al. 2020

Preprint

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Agonist-activated G protein-coupled receptors (GPCRs) must correctly select from hundreds of potential downstream signaling cascades and effectors. To accomplish this, GPCRs first bind to an intermediary signaling protein, such as G protein or arrestin. These intermediaries initiate signaling cascades that promote the activity of different effectors, including several protein kinases. The relative roles of G proteins versus arrestins in initiating and directing signaling is hotly debated, and it remains unclear how the correct final signaling pathway is chosen given the ready availability of protein partners. Here, we begin to deconvolute the process of signal bias from the dopamine D1 receptor (D1R) by exploring factors that promote the activation of ERK1/2 or Src, the kinases that lead to cell growth and proliferation. We found that ERK1/2 activation involves both arrestin and Gas, while Src activation depends solely on arrestin. Interestingly, we found that the phosphorylation pattern influences both arrestin and Gas coupling, suggesting an additional way the cells regulate G protein signaling. The phosphorylation sites in the D1R intracellular loop 3 are particularly important for directing the binding of G protein versus arrestin and for selecting between the activation of ERK1/2 and Src. Collectively, these studies correlate functional outcomes with a physical basis for signaling bias and provide fundamental information on how GPCR signaling is directed. Significance Statement:The functional importance of receptor phosphorylation in GPCR regulation has been demonstrated. Over the past decade, the phospho-barcode concept was developed to explain the multidimensional nature of the arrestin-dependent signaling network downstream of GPCRs. Here, we used the dopamine-1 receptor (D1R) to explore the effect of receptor phosphorylation on G protein-dependent and arrestin-dependent ERK and Src activation. Our studies suggest that D1R intracellular loop-3 phosphorylation affects both G proteins and arrestins. Differential D1R phosphorylation can direct signaling toward ERK or Src activation. This implies that phosphorylation induces different conformations of receptor and/or bound arrestin to initiate or select different cellular signaling pathways. \body Although it is tempting to divide GPCR signaling into these two branches, G protein-dependent and arrestindependent, the nature of signaling in the cell is much more complex (reviewed in (1, 7, 8)). As a result, this classical paradigm does not fully explain the range of biological responses observed when a GPCR is activated. For example, agonist identity can affect the recruitment of different G-proteins or arrestins, which determines the selection of downstream effectors (9). In addition, some activated GPCRs may interact directly with non-canonical signaling partners, including Src-family kinases (10-21). There are also numerous studies suggesting a specific role for the nonvisual arrestins in receptor-independent activation of ERK1/2, AKT, JNK3, and NF-kB (6,(22...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

Kaya

Perry

Gurevich

et al. 2020

Preprint

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“…Overall, GPCR‐arrestin complexes are highly dynamic and the biophysical determination of their structure is technically very challenging. To date, only a few 3D structures of arrestin–GPCR complexes have been solved: the crystal structure of the rhodopsin (Rho)‐bound arr1 (Kang et al , 2015; Zhou et al , 2017), and the three very recent cryo‐electron microscopy (cryo‐EM) structures of βarr1 in complex with the class B NTS 1 R (Yin et al , 2019; Huang et al , 2020), the muscarinic acetylcholine‐2‐receptor (M 2 R) (Staus et al , 2020), and the β 1 ‐adrenoceptor (β 1 ‐AR) (Lee et al , 2020). The β 1 ‐AR belongs to class A arrestin binders (Shiina et al , 2000, Eichel et al , 2016), whereas contradictory findings have been reported for the M 2 R (Gurevich et al , 1995, Jones et al , 2006).…”

Section: Introductionmentioning

confidence: 99%

Exploring GPCR‐arrestin interfaces with genetically encoded crosslinkers

et al. 2020

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β‐arrestins (βarr1 and βarr2) are ubiquitous regulators of G protein‐coupled receptor (GPCR) signaling. Available data suggest that β‐arrestins dock to different receptors in different ways. However, the structural characterization of GPCR‐arrestin complexes is challenging and alternative approaches to study GPCR‐arrestin complexes are needed. Here, starting from the finger loop as a major site for the interaction of arrestins with GPCRs, we genetically incorporate non‐canonical amino acids for photo‐ and chemical crosslinking into βarr1 and βarr2 and explore binding topologies to GPCRs forming either stable or transient complexes with arrestins: the vasopressin receptor 2 (rhodopsin‐like), the corticotropin‐releasing factor receptor 1, and the parathyroid hormone receptor 1 (both secretin‐like). We show that each receptor leaves a unique footprint on arrestins, whereas the two β‐arrestins yield quite similar crosslinking patterns. Furthermore, we show that the method allows defining the orientation of arrestin with respect to the GPCR. Finally, we provide direct evidence for the formation of arrestin oligomers in the cell.

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“…In several structures of the receptor-arrestin complexes, the polar core arginine does not interact with the receptor-attached phosphates (Huang et al, 2020;Kang, Zhou, & Gao, 2015;Staus et al, 2020;Yin et al, 2019;Zhou et al, 2017). Instead, a lysine (Lys301 in mouse arrestin-1, homologous to Lys300 in bovine arrestin-1, Lys294 in arrestin-2, and Lys295 in arrestin-3) on the "lariat loop" (Hirsch et al, 1999) was found in direct contact with one of the phosphates in the phosphorylated receptors.…”

mentioning

confidence: 99%

Lysine in the lariat loop of arrestins does not serve as phosphate sensor

Vishnivetskiy

Chen

May

et al. 2020

Journal of Neurochemistry

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Protein-protein interactions govern virtually all essential cellular functions. In most cases, proteins bind only a certain functional state of their partners, while "ignoring" other states. Thus, elucidation of molecular mechanisms whereby one protein "selects" a particular functional state of its binding partner has general biological significance. Arrestins are among the most studied proteins in this regard. Arrestins selectively interact with phosphorylated and activated forms of their cognate G-protein-coupled receptors (GPCRs), binding them with much higher affinity than the same receptors when they are inactive or unphosphorylated (reviewed in (Carman & Benovic, 1998; Gurevich & Gurevich, 2004)). Vertebrates express four arrestin isoforms: two specialized visual in photoreceptors, arrestin-1 1 and-4, and two ubiqui-1 We use systematic names of arrestin proteins, where the number after the dash indicates the order of cloning: arrestin-1 (historic names S-antigen, 48 kDa protein, 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).

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A complex structure of arrestin-2 bound to a G protein-coupled receptor

Cited by 176 publications

References 46 publications

Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

Exploring GPCR‐arrestin interfaces with genetically encoded crosslinkers

Lysine in the lariat loop of arrestins does not serve as phosphate sensor

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