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domain.
125
For the DSCR3 paralogue of some species such as
Dictyostelium
,
it is possible to detect both a VPS26 domain (expect value
10
43
)
and an overlapping arrestin-N domain (expect value
¼
4.66
10
4
), a prop-
erty also observed for human DSCR3 (
Fig. 2.3
A). The modeled structure of
DSCR3 is indeed very close to that of VPS26 (
Fig. 2.3
B).
9
In a phylogenetic
tree (
Fig. 2.2
), the DSCR3 clade is the first group to split off the arrestin
branch that gives rise to the VPS26 branch, placing DSCR3 as a possible
“missing link” between arrestins and VPS26.
DSCR3 has been suggested to function as a signaling platform reminis-
cent of arrestin in a novel MAPK signaling pathway, by acting as a scaffold
for DYRK1A as MAPK, SNF1LK as MKK, and RIP4 as MKKK.
125
¼
2.91
4.3. RGP1, yet another arrestin-fold protein
It was of obvious interest to screen the whole human genome for still
unknown candidate proteins with an arrestin fold. A recent tool, BackPhyre
developed by Phyre2
(
http://www.sbg.bio.ic.ac.uk/phyre2
), allows one to
search a known structure against a wide range of genomes. When this mode
was used on the human genome, retrograde Golgi transport protein (RGP1)
emerged as a potential arrestin-fold protein. Blast searches identified RGP1
in protists, plants, fungi, yeast, and metazoan.
A phylogenetic tree (
Fig. 2.2
), built on the basis of a Clustal Omega
alignment (
http://www.ebi.ac.uk/Tools/msa/clustalo/
)
, revealed a new
RGP1 sector branching off the ART proteins, and close to the VPS26 clade.
Structure threading and modeling qualify RGP1 as a novel arrestin-fold pro-
tein. Indeed, the secondary structure of RGP1 as predicted by PsiPred is
very close to that of VPS26 and consists essentially of a succession of posi-
tionally conserved
b
-strands (
Fig. 2.6
). RGP1 could be modeled with a con-
fidence value above 99% on several templates, VPS26, visual- and
b
-arrestins, and visually, the structure of RGP1 unambiguously looks alike
the characteristic structure of VPS26.
RGP1 forms a heterodimer with Ric1p to function as a nucleotide
exchange factor (GEF) for Ypt6, the yeast homolog of mammalian Rab6.
Activated Ypt6 then recruits the Golgi-associated retrograde protein tether-
ing complex GARP and controls, together with Arl1, the tethering events at
the trans-Golgi cisternae of incoming vesicles carrying over Golgi mem-
brane proteins from endosomes.
126,127
Two arrestin-fold proteins seem thus to be involved, although with very
different functions, at the two ends of the retrograde transport pathway
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