True Arrestins and Arrestin-Fold Proteins: A Structure-Based Appraisal - Progress in Molecular Biology and Translational Science - page 31

3.3. Amoebal ADCs
The amoeba Dictyostelium discoideum possesses 55 GPCRs, 90 but no true
arrestin. Instead, it harbors six genes encoding arrestin domain-containing
proteins (AdcA-F) as well as VPS26 and DSCR3 (VPS26L) genes. 9,91
The amoebal ADC proteins are characterized by extensions on both sides
of the central arrestin core, with various protein-protein or protein-lipid
interaction domains depending on the isoforms, such as C2, LIM, MIT,
or FYVE domains. 9 The expression of AdcA-F is developmentally regu-
lated ( http://dictybase.prg ) . AdcA, -C, and -D are found in the proteome
of the vegetative endocytic pathway. 92
The multiple domains of AdcA structure have successfully been modeled
on several templates with the Phyre2 software in the intensive mode
( Fig. 2.5 ). The assembled structure shows the three independent domains:
the His domain, the arrestin core, and the FYVE domain. Their respective
positioning based essentially on ab initio -modeled residues is not yet supported
by experimental evidence. In arrestins, b -strand 20 is folded as to form the
N-domain together with b -strands 1-10, resulting in the relative proximity
of N- and C-domains in the inactive state. The model of AdcA built on the
arrestin structure copies this neighborhood. The N-terminal side triple-
polyhistidine cluster is involved in the oligomerization of AdcA (Guetta D.,
Klein G. & Aubry L., unpublished results) and its C-terminal FYVE domain
targets the protein to early endosomes. 91 It is tempting to assume that the asso-
ciation of the C-terminal FYVE domain with endosomal PI(3)P or the oligo-
merization of the histidine-rich N-terminus influences the overall structure of
theprotein, andpossibly the accessibility of bindingpartners to the arrestin core.
Whether AdcA regulates membrane cargoes is not known, even though its
massive presence at the endosomal membrane fits with such a hypothesis.
4. OTHER ARRESTIN-FOLD PROTEINS
4.1. VPS26, a component of the retromer
The retromer was first described in yeast and characterized as a coat complex
required for the retrieval of the lysosomal hydrolase receptor VPS10 from
endosomes and its retrograde transport to the trans-Golgi network
(TGN). 93 It was later described in mammals, where it shuttles the cation-
independent mannose-6-phosphate receptor, CI-MPR, from endosomes
to the TGN. 94 The composition of retromers is conserved from yeast to