Cited by 382Receptor Mechanisms and SignalingNeuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase Signaling

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Structure of the neurotensin receptor 1 in complex with β-arrestin 1

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Huang, Weijiao, Masureel, Matthieu, Qu, Qianhui, Janetzko, John, Inoue, Asuka, Kato, Hideaki E., Robertson, Michael J., Nguyen, Khanh C., Glenn, Jeffrey S., Skiniotis, Georgios, Kobilka, Brian K.·2020·Nature

DOI 10.1038/s41586-020-1953-1PMC PMC7100716

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Abstract

Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways 1,2. Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with βarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin-arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin-receptor interactions.

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Effects of Membrane Cholesterol on the Structure and Function of Selected Class A GPCRs─Challenges and Future Perspectives
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Self-citation
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Signaling-Biased and Constitutively Active Dopamine D2 Receptor Variant
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β-arrestin–dependent PI(4,5)P 2 synthesis boosts GPCR endocytosis
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“About this proposal, another group suggested that conversion of PI(4,5)P2 to PI(3,4)P2 and PI(3)P is not likely until dynamin completes the scission of a CCP because lipid molecules would be exchanged rapidly between the PM and stillconnected clathrin-coated vesicles (14).”
BackgroundMethodInfluential
Single-molecule FRET and conformational analysis of beta-arrestin-1 through genetic code expansion and a Se-click reaction
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Activation of ventral tegmental area neurotensin Receptor-1 neurons promotes weight loss
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“A cysteine-free bovine β arr1 wasgeneratedbyintroducingthemutationsC59A, C125S, C140I, C150V, C242V, C251V, and C269S to enhance the expression level and protein stability 24,32,37 .”
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GPCR Binding and JNK3 Activation by Arrestin-3 Have Different Structural Requirements
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“Conserved lariat loop lysine (Lys-294 and Lys-295 in arrestin-2 and -3, respectively) interacts with a phosphate in bound phosphopeptide [42], bound GPCRs [34, 53-56] (Fig.”
Self-citation
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“…binding states that better fit the endosomal membrane curvature (Tsutsumi et al., 2022), similar to the neurotensin receptor 1 – β -arrestin complex (Huang et al., 2020), with previous observations that US28 constitutively internalizes in a β -arrestin- independent manner (Droese et al., 2004;…”
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“The structure of the finger loop in basal bovine arrestin-1 (Arr1 basal; PDB 1CF4 [24]), mouse arrestin-1 in complex with rhodopsin (Arr1-Rho, PDB 5W0P [6]), basal arrestin-2 (Arr2 basal, PDB 1G4M [25]), arrestin-2 in complex with M2 muscarinic (Arr2-M2R; PDB 6U1N [8]), β1-adrenergic (Arr2-β1AR; PDB 6TK0 [9]), and NTS…”
BackgroundInfluential
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“To engage with the receptor, the finger and middle loops of the N-terminal domain, as well as the C and lariat loops of the C-terminal domain, interact with the cleft of the intracellular face of C5aR1 (Huang et al. 2020).”
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Structural characterization of five functional states of metabotropic glutamate receptor 8
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Self-citation
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“In the last decade, there has been outstanding progress in the determination of crystal and cryo-EM structures of GPCRs mostly in the apo form, but also in complex with ligands, and even with intracellular binding partners such as G proteins or arrestins (Venkatakrishnan et al., 2013; Hilger et al., 2018; Shimada et a…”
Background
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“However, in complex with neurotensin receptor NTSR1, bound arrestin-2 was turned by 85–90 ◦ relative to this orientation [88,90].”
BackgroundInfluential
Flavors of GPCR signaling bias
Seyedabadi, M., & Gurevich, V. V. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110167 · Cited by 12
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“26,27 After b -arrestin binding, the GPCR/ b -arrestin complex can form a partial engagement, when only the phosphorylated C-terminal tail of the GPCR interacts directly with the N-domain of the b -arrestin, or a core engagement, which also involves insertion of the ﬁnger loop of the b - arrestin…”
GPCR targeting of E3 ubiquitin ligase MDM2 by inactive β-arrestin
Yun, Y., Yoon, H., Jeong, Y., Choi, Y., Jang, S., Chung, K. Y., & Lee, H. H. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2301934120 · Cited by 12
“…phosphorylated C-tails [V 2 Rpp derived from the vasopressin receptor 2, PDB code 4JQI (40); NTSR1 derived from neurotensin receptor 1, PDB code 6PWC (37); HTR2B derived from the 5-HT 2B serotonin receptor, PDB code 7SRS (34)] bound to β arr1, we compared the conformations of these structures (Fig.”
Influential
A genetically encoded small-size fluorescent pair reveals allosteric conformational changes of G proteins upon its interaction with GPCRs by fluorescence lifetime based FRET
Shi, P., Zhang, Y., Lv, P., Fang, W., Ling, S., Guo, X., Li, D., Liu, S., Sun, D., Zhang, L., et al. (2020) · Chemical Communications · doi:10.1039/d0cc02691c · Cited by 12
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C5aR2 receptor: The genomic twin of the flamboyant C5aR1
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Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners
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“Notable exemplars are the mammalian arrestins, which can be found as monomers (PDB entry 3P2D 46 ), as isoform-speci ﬁ c trimers (PDB entry 5TV1 47 ), or in complex with each of >800 receptors 48,49 .”
The structural basis of the G protein–coupled receptor and ion channel axis
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“In other GPCR-arrestin complexes, the interactions between ICL2 and the finger loop continue to demonstrate a conservative effect (Staus et al., 2020; Huang et al., 2020).”
Distinct activation mechanisms of CXCR4 and ACKR3 revealed by single-molecule analysis of their conformational landscapes
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Arrestin‐centred interactions at the membrane and their conformational determinants
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“Indeed, PIP 2 and PIP 3 have been shown to potentiate and stabilise active-state β -arrestins, specifically when bound to active receptors (Huang et al., 2020; Janetzko et al., 2022).”
Influential

Authors: Huang, W., Masureel, M., Qu, Q., Janetzko, J., Inoue, A., Kato, H. E., Robertson, M. J., Nguyen, K. C., Glenn, J. S., Skiniotis, G., & Kobilka, B. K.
Affiliations: Stanford Medicine (US)
Tohoku University (JP)
Stanford University (US)
SLAC National Accelerator Laboratory (US)
Corresponding author: Skiniotis, Georgios
Kobilka, Brian K.
ORCID: Huang, Weijiao
Masureel, Matthieu
Qu, Qianhui
Janetzko, John
Inoue, Asuka
Kato, Hideaki E.
Glenn, Jeffrey S.
Skiniotis, Georgios
Kobilka, Brian K.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2020-01-16
Volume: 579
Issue: 7798
Pages: 303-308
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-020-1953-1
PMC: PMC7100716
OpenAlex: W3000145087
Cited by: 373
References: 58
Citations by year: 2026: 45 · 2025: 66 · 2024: 41 · 2023: 63 · 2022: 47 · 2021: 63 · 2020: 46
FWCI: 17.62
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (5u19ai109662-05)
Japan Society for the Promotion of Science (19H03163, 17K08264)
National Cancer Institute (P30CA124435)
National Institute of Allergy and Infectious Diseases (U19-AI109662)
National Institute of Neurological Disorders and Stroke (R01NS028471)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: neurotensin receptor 1, β-arrestin1, G protein-coupled receptors, receptor phosphorylation, phosphatidylinositol 4,5-bisphosphate, receptor internalization, cryo-EM structure
MeSH terms: beta-Arrestin 1, Humans, Models, Molecular, Phosphorylation, Receptors, Neurotensin, Cryoelectron Microscopy, Protein Structure, Quaternary, Protein Stability

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Structure of the neurotensin receptor 1 in complex with β-arrestin 1

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