True Arrestins and Arrestin-Fold Proteins: A Structure-Based Appraisal - Progress in Molecular Biology and Translational Science - page 27

putative structure of the different human ARRDCs and VDUP and
extended our previous work. 9 The relevance of modeled structures is highly
dependent on the coverage of the modeled structure and the confidence
level. The core of all human ARRDCs (including TXNIP) could be
modeled with a high confidence level ( > 99%). The coverage of the modeled
structures ranged from 65% to over 90% of the full-length proteins due to
extensions matching with no known structural domains ( Fig. 2.3 A). In all
cases, a structure composed of a two-module b -strand sandwich was recog-
nizable ( Fig. 2.3 B). No reliable information could be obtained at the level of
the interface between the N- and C-domains, especially in terms of neigh-
boring charged amino acids (polar core).
Because of their recent discovery, little is known about the molecular
function of ARRDCs and available data are restricted to the human
isoforms, which play a physiological role in the regulation of metabolism. 78
Among all arrestin domain-containing proteins, only ARRDC2 and its
paralogues in other species harbor a C-terminal cysteine predicted to be
S-nitrosylated ( http://sno.biocuckoo.org/ ). Human ARRDCs do not share
consensus SUMOylation motifs.
TXNIP and all ARRDCs except ARRDC5 harbor two [L,P]PxY sites
that are able to bind WWdomains generally found in HECT-type ubiquitin
ligases. ARRDC1-4 and TXNIP do interact with several E3 ubiquitin
ligases: WWP1, WWP2, Nedd4, and Itch (except ARRDC2 and
ARRDC4 that lack interaction with WWP2 and Itch). 79 ARRDC1 is
ubiquitinated by WWP1 79 and WWP2. 80 Besides binding ubiquitin ligases
and being a target for their ubiquitination, ARRDCs also serve as a platform
for the ubiquitination of their cargoes. ARRDC3 binds to the activated,
phosphorylated form of b -4 integrin and controls its endocytosis,
ubiquitination, and final degradation. 81 ARRDC3 also recruits the
ubiquitin E3 ligase Nedd4 to mediate ubiquitination of the b 2 -adrenergic
receptor, an essential step in its degradation. 82 An analysis of glucose uptake
showed that it was inhibited by TXNIP and ARRDC4, suggesting their
possible role in the endocytosis of glucose transporter, but

their

WW-binding domains were dispensable for that inhibition. 83
ARRDC1-4 and TXNIP proteins show interactions with subunits
of the ESCRT machinery, namely, Alix and Tsg101 (known as VPS23 in
yeast). The current hypothesis is that ARRDC1 is involved at the PM in
PPxY-dependent viral budding by bridging HECT ubiquitin ligases
and ESCRT-III components. 79 Interestingly, cells are able to shed in a
virus-independent process microvesicles (ARMMs, ARRDC1-mediated