Arrestins and Protein Ubiquitination - Progress in Molecular Biology and Translational Science - page 191

within the core of the molecule, which are disrupted upon binding of phos-
phate moieties on the phosphorylated 7TMR intracellular domains leading
to “activation” or conformational changes in arrestins that allow them to
exhibit agonist-induced effects. 109-113 Although VPS26 has a polar core,
the composition and surrounding structural elements are different and sim-
ilar 7TMR-dependent conformational change and activation do not appear
to be plausible for VPS26. 108 Nonetheless, these similar topologies predict
some functional analogy between VPS26 and arrestins in terms of cargo traf-
ficking, which awaits further characterization.
Arrestin domain structure is also predicted for Down syndrome critical
region 3, a nuclear protein involved in partial or complete trisomy found in
Down syndrome. 100 This protein has not been studied in any great detail so
far, but there are indications of a role in transcription and/or MAPK
signaling.
Six related proteins called arrestin domain-containing proteins 1-5
(ARRDC1-5) and thioredoxin-interacting protein or TXNIP (also known
as vitamin D up regulated protein, VDUP1) also contain regions with the
arrestin N- and C-terminal domain signatures but share very little sequence
identity (11-15%) with arrestins. 100 With the exception of ARRDC5, these
proteins have polyproline motifs and interact with WW domain-containing
E3 ubiquitin ligases. 114-117 TXNIP, with predominant nuclear distribution,
and ARRDC1, with plasma membrane localization, do not interact with the
agonist-activated b 2 AR. 118 However, three members that show endosomal
distribution, ARRDC2, ARRDC3, and ARRDC4, can bind with internal-
ized b 2 ARs on endosomes. 118 These ARRDC proteins are localized in
endocytic vesicles that are associated with a protein called hepatocyte growth
factor-regulated substrate (HRS), and this binding also requires polyproline
motif in the ARRDC proteins. Studies show that in the case of the b 2 AR,
b -arrestin2 acts as the primary adaptor for recruiting Nedd4 to ubiquitinate
the b 2 AR and that overexpressed ARRDC proteins (one or more of
ARRDC2, -3, and -4) are subsequently recruited to the internalized
b 2 AR on endosomes. 118 This recruitment to the internalized b 2 AR is
abolished when the polyproline motifs in these ARRDC proteins are altered
such that their binding to the Nedd4 WW domain is lost. 118 Thus, although
domain-domain interactions predict recruitment of Nedd4 to the b 2 AR via
ARRDC proteins, experimental evidence points to an alternate mechanism:
Nedd4 bound to the b 2 AR complex recruits ARRDC positive endosomes
to traffic-ubiquitinated b 2 ARs into HRS-positive endosomes. Furthermore,
gene silencing of ARRDC3 had no effect on

b 2 AR degradation or