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Review
. 2022 Jan 17;23(2):1000.
doi: 10.3390/ijms23021000.

Scaffolding of Mitogen-Activated Protein Kinase Signaling by β-Arrestins

Affiliations
Review

Scaffolding of Mitogen-Activated Protein Kinase Signaling by β-Arrestins

Kiae Kim et al. Int J Mol Sci. .

Abstract

β-arrestins were initially identified to desensitize and internalize G-protein-coupled receptors (GPCRs). Receptor-bound β-arrestins also initiate a second wave of signaling by scaffolding mitogen-activated protein kinase (MAPK) signaling components, MAPK kinase kinase, MAPK kinase, and MAPK. In particular, β-arrestins facilitate ERK1/2 or JNK3 activation by scaffolding signal cascade components such as ERK1/2-MEK1-cRaf or JNK3-MKK4/7-ASK1. Understanding the precise molecular and structural mechanisms of β-arrestin-mediated MAPK scaffolding assembly would deepen our understanding of GPCR-mediated MAPK activation and provide clues for the selective regulation of the MAPK signaling cascade for therapeutic purposes. Over the last decade, numerous research groups have attempted to understand the molecular and structural mechanisms of β-arrestin-mediated MAPK scaffolding assembly. Although not providing the complete mechanism, these efforts suggest potential binding interfaces between β-arrestins and MAPK signaling components and the mechanism for MAPK signal amplification by β-arrestin-mediated scaffolding. This review summarizes recent developments of cellular and molecular works on the scaffolding mechanism of β-arrestin for MAPK signaling cascade.

Keywords: MAPK; arrestin; protein structure; scaffold.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Comparison of GPCR-arrestin and GPCR-G-protein complexes. (A) The structure of the neurotensin receptor-1 (NTSR1, red) and β-arrestin-1 (green) complex (PDB: 6UP7). (B) The structure of the NTSR1 (red) and heterotrimeric Gi1(light pink) complex (PDB: 7L0Q).
Figure 2
Figure 2
The structures of β-arrestin and the scaffolding mechanism of ERK1/2 signaling cascade. (A) The structure of β-arrestin 1 in the basal state (PDB: 1G4R). The C-terminal βXX strand is colored in orange. (B) Comparison of β-arrestin in the basal and active states. The structures of β-arrestin 1 in basal (grey, PDB: 1G4R) and NTSR1-bound active (green, PDB: 6UP7) states are compared. The loops on β-arrestin 1 are colored as follows: finger loop, brown; middle loop, dark blue; gate loop, purple; lariat loop, salmon. (C) The representation of cRaf domains (left) and conformational changes of cRaf upon Ras binding (right). (D) The proposed model of the scaffolding mechanism of ERK1/2 signaling cascade by β-arrestin 1. (i) cRaf is auto-inhibited by the N-terminal domains, including RBD and CRD. (ii) cRaf RBD interacts with the back loop of β-arrestin 1. (iii) The phosphorylated GPCR may bind to β-arrestin 1. (iv) The N-lobe of MEK1 interacts with the interdomain loop I of β-arrestin 1. (v) The activated β-arrestin 1 interacts with ERK1/2 between the gate loop of β-arrestin 1 and the N-lobe of ERK1/2 and the interdomain loop II of β-arrestin 1 and the C-lobe of ERK1/2.
Figure 3
Figure 3
The JNK3 signaling scaffolding mechanism of β-arrestin 2. (A) The β-arrestin 2 structure with first 25 residues highlighted with blue (PDB: 3P2D). (B) The conveyor belt model of JNK3 signaling scaffolding mechanism of β-arrestin 2.
Figure 4
Figure 4
Distinct downstream signaling effects that are mediated by different phosphorylation patterns of GPCRs. (A) The four known phosphate-binding pockets on arrestins. The structure of CXCR7 phosphopeptide (red) and the activated β-arrestin 2 (green) complex (PDB: 6K3F) is shown as a representative structure. The conserved positively charged pockets on arrestins (pocket A, B, and F) are shown in the dashed black circles. The newly identified phosphate-binding pocket P on β-arrestin 2 is shown in the purple square. (B) Differently phosphorylated GPCRs induce differently activated β-arrestins, leading to distinct downstream signaling effects.

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