True Arrestins and Arrestin-Fold Proteins: A Structure-Based Appraisal - Progress in Molecular Biology and Translational Science - page 35

with multiple VPS29 and VPS35 isoforms. 108 The reason for such complex-
ity in these unicellular organisms is unclear.
SNXs used in retromer-dependent retrograde transport are members of
the SNX-BAR subfamily and contain two membrane-binding domains: a
phosphatidyl inositide-binding PX (Phox homolog) and a membrane-
curvature sensing domain BAR (Bin/Amphyphisin/Rvs). BAR domains
are found in endophilins and retromer-associated SNXs. They usually form
a dimer that senses and generates membrane curvature. The function of the
BAR domain is to drive tubulation of the endosomal membrane, an early
step in the formation of the endosomal vesicles due to retrograde transport
toward the TGN. 106 Recently, new sorting nexins (SNX3, SNX27) that
contain no BAR domain have been shown to associate with the cargo-
selective subunits of the retromer and to confer cargo specificity. 107,113-115
SNX-coated tubule formation and fission of cargo-enriched vesicles due
to retrograde transport are dependent on the actin cytoskeleton to generate
the mechanical force for tubulation and scission. 110,116,117 SNXs directly
interact with p150 glued , a component of the dynactin-dynein microtubule
motor. 118,119 Microtubules provide the long-range tracks for retrograde
transport. 114
Recent evidence suggests a role for clathrin in retrograde trafficking of
the Shiga toxin and CI-MPR via a partnership with the DNA-J domain-
containing protein RME-8. 120-122 A RME-8-dependent association of
SNX1 of the retromer with the ESCRT-0 subunit Hrs may provide the pos-
sibility for a cargo to follow the retrograde transport pathway or to be sorted
by the ESCRT machinery for degradation, depending on the adequate
stimulus. 120,123
At the TGN, the mammalian GARP (Golgi-associated retrograde pro-
tein) complex plays a role in the delivery of Golgi proteins sorted by the
retromer, at least for the CI-MPR and the Shiga toxin. 124
4.2. DSCR3, a VPS26-related protein
Down syndrome is a consequence of a partial or full trisomy of chromosome
21, characterized by facial morphological features, muscular hypotonia, and
mental retardation. DSCR3 (for Down syndrome critical region gene 3) is
one of the proteins that is lost in this syndrome.
DSCR3 has 10-17% identity and 17-27% homology with the a -/ b -
arrestins, the closest proteins being VPS26A (14.8% identity) and ARRDC5
(16.9% identity). DSCR3 has been predicted to harbor a VPS26 PFAM