C-edge loops of arrestin function as a membrane anchor

Lally, Ciara C. M.; Bauer, Brian; Selent, Jana; Sommer, Monika

doi:10.1038/ncomms14258

Cited by 85 publications

(102 citation statements)

References 52 publications

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“…The Arr2-NTSR1 complex is formed by asymmetric assembly of the two components with the horizontal axis of Arr2 intersecting the inner surface of the cell membrane at about 20°, resulting in the interaction of the hydrophobic C-edge loops (L191 and M192, and L334 through L338) of the arrestin with the cell membrane (Fig 2a&b). This is consistent with the crystal structure of visual arrestin-rhodopsin complex, which for the first time displayed the asymmetric arrestin-GPCR assembly and confirmed the function of the hydrophobic C-edge loops of arrestin as a membrane anchor that stabilizes the binding of arrestin to membrane-embedded receptor, which was later confirmed experimentally 7,26,27 . The interaction of the hydrophobic C-edge loops of the Arr2 with cell membrane layer suggests that the lipid binding capability is a general property of the arrestin family members.…”

Section: The Overall Structure Of the Arr2-ntsr1 Complexsupporting

confidence: 87%

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

Yin

Jin

et al. 2019

Preprint

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Arrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are β-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2-NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2-NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.

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Section: The Overall Structure Of the Arr2-ntsr1 Complexsupporting

confidence: 87%

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

Yin

Jin

et al. 2019

Preprint

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“…Importantly, we observed electron density for the membrane-touching loop of arrestin (C-edge loop) from residue 340 through 342 (Figure S1C). Molecular dynamics simulation indicated that C-edge loops of arrestin function as membrane anchors, whose engagement with membrane is required for GPCR binding by arrestins (Lally et al, 2017). We also observed electron density for poly N-acetyl-D-glucosamine at the N15 glycosylation site of each rhodopsin molecule (Figure S1D), and most of the rhodopsin C-terminal tail (residues 330–343) including two phosphate groups at T336 and S338 (Figures 1, 2 and S1E–F).…”

Section: Resultsmentioning

confidence: 99%

Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors

Zhou

Waal

et al. 2017

Cell

377

548

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SUMMARY G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor’s C-terminal tail. Here we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin–arrestin complex, in which the phosphorylated C-terminus of rhodopsin forms an extended intermolecular β-sheet with the N-terminal β-strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.

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“…We verified biochemically that PIP2 binding to this determinant is sufficient to partition β-arrestin out of the solution phase (Extended Data Figure 6e, f). This phosphoinositide-binding determinant is specific to β-arrestins but a lipid-anchoring region in the C-domain was recently identified visual arrestin 33 . Mutating the homologous residues in β-arrestin did not prevent accumulation at the plasma membrane or in CCSs (Extended Data Table 1; Extended Data Figure 6g, h).…”

Section: Capture After Gpcr Dissociationmentioning

confidence: 99%

Catalytic activation of β-arrestin by GPCRs

Eichel

Jullié

Barsi‐Rhyne

et al. 2018

Nature

192

184

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β-arrestins are critical regulator and transducer proteins for G protein-coupled receptors (GPCRs). Cellular β-arrestin function is presently thought to require stable and stoichiometric GPCR/β-arrestin scaffold complex formation driven by the phosphorylated GPCR tail. We demonstrate a distinct and additional mechanism that does not require stable GPCR/β-arrestin scaffolding or the GPCR tail. Instead, it is activated by transient engagement of the GPCR core that destabilizes a conserved inter-domain charge network in β-arrestin. This promotes capture of β-arrestin at the plasma membrane and accumulation in clathrin-coated endocytic structures (CCSs) after GPCR dissociation, requiring a series of β-arrestin interactions with membrane phosphoinositides and CCS lattice proteins. β-arrestin clustering in CCSs without its upstream activating GPCR is associated with a β-arrestin-dependent component of the cellular ERK (Extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular β-arrestin function that is activated catalytically by GPCRs.

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C-edge loops of arrestin function as a membrane anchor

Cited by 85 publications

References 52 publications

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

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

Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors

Catalytic activation of β-arrestin by GPCRs

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