Arrestins: A Small Family of Multi-Functional Proteins

Abstract

The first member of the arrestin family, visual arrestin-1, was discovered in the late 1970s. Later, the other three mammalian subtypes were identified and cloned. The first described function was regulation of G protein-coupled receptor (GPCR) signaling: arrestins bind active phosphorylated GPCRs, blocking their coupling to G proteins. It was later discovered that receptor-bound and free arrestins interact with numerous proteins, regulating GPCR trafficking and various signaling pathways, including those that determine cell fate. Arrestins have no enzymatic activity; they function by organizing multi-protein complexes and localizing their interaction partners to particular cellular compartments. Today we understand the molecular mechanism of arrestin interactions with GPCRs better than the mechanisms underlying other functions. However, even limited knowledge enabled the construction of signaling-biased arrestin mutants and extraction of biologically active monofunctional peptides from these multifunctional proteins. Manipulation of cellular signaling with arrestin-based tools has research and likely therapeutic potential: re-engineered proteins and their parts can produce effects that conventional small-molecule drugs cannot.

Keywords: GPCR; MAP kinase; arrestin; microtubules; ubiquitin ligase.

Figure 1

Functional elements of arrestins. Crystal structure of bovine arrestin-2 (PDB ID 1G4M [49]). Functional elements are indicated as follows: residues in the polar core (Asp26, Arg169, Asp290, Asp297; Arg 393 in the C-terminus is not resolved in this monomer and therefore is not shown) and three-element interaction (Val8 and Phe9 in β-strand I; Leu100, Leu104, and Leu108 in the α-helix; and Ile386, Val387, and Phe388 in the C-terminus are not resolved in the structure of this monomer and therefore are not shown) are shown as CPK models, and Lys10, Lys11, and Lys294, as well as C-edge residues 190–192 and N-edge residues 157–161 are shown as stick models. The following elements are highlighted by color: the finger loop (residues 64–74; red), the middle loop (residues 129–139; light blue), the lariat loop (residues 275–316; light red), N-edge (residues 157–161; orange), C-edge (residues 190–192; pink; note that the other C-edge loop, residues 334–338, is not shown because it is not resolved in the structure of this monomer), and inter-domain hinge region (residues 173–184; yellow). The chemical nature of the modeled residues is shown, as follows: hydrophobic, yellow; positively charged, dark blue; negatively charged, bright red. Image was created in DS ViewerPro 6.0 (Dassault Systèmes, San Diego, CA, USA).

Figure 2

Binding selectivity of arrestins. The binding of arrestin-1 to rhodopsin, arrestin-2 to M2 muscarinic receptor (M2R), and arrestin-3 to β2-adrenergic receptor (b2AR) is shown. Functional forms of the receptors are indicated, as follows: P, inactive phosphorylated; P*, activated phosphorylated; -, inactive unphosphorylated; *, activated unphosphorylated.

Figure 3

Arrestin elements that determine receptor preference. These were identified in [105]: arrestin-1 residues 49–90 in the N-domain and 237–268 in the C-domain, and homologous arrestin-2 residues 45–86 and 233–262. The structures are shown as solid ribbons. Receptor-discriminator elements are shown in red on the structure of arrestin-1 (PDB ID 1CF1 [20]) and arrestin-2 (PDB ID 1G4M [49]). The remaining arrestin-1 and -2 molecules are shown in blue. Images were created in DS ViewerPro 6.0 (Dassault Systèmes, San Diego, CA, USA).