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and polar core, VPS26 is generally not the cargo-recognition subunit in the
retromer. Most examples of retromer-cargo interactions use the recognition
by VPS35 of a specific [FW]L[MV] sequence carried by the cargoes.
96
VPS26 functions rather as an adaptor linking VPS35 and SNXs. There is,
however, a recent example in which VPS26 directly binds a cargo. SorlA,
a member of the VPS10 receptor family, transports the amyloid precursor
protein to the Golgi for its processing by
a
-secretase. In the absence of ret-
rograde transport, the amyloid precursor protein is transported to the lyso-
some where it is processed by
b
- and
g
-secretases into the neurotoxic
amyloid
b
peptide agent of Alzheimer's disease. VPS26 is the retromer sub-
unit that recognizes SorlA's sorting motif FANSHY.
132
Interestingly,
FANSHY is an extension of the FLV sequence previously identified on
sortilin and CI-MPR and the same distance between two aromatic residues
can be found in the extended FLV motif.
132
Substantial evidence demon-
strates a role for clathrin and its adaptor epsinR in retromer trafficking.
120,152
The role of the adaptor AP-1 is still debated.
114,152
Tubulation of cargo-
enriched endosomal patches and formation of the recycling endosomal ves-
icles proceed by a retromer-specific mechanism that takes advantage of the
SNX's membrane-bending property. There is to our knowledge no evi-
dence for posttranslational modifications of the retromer subunits or the
transported cargoes, besides the CI-MPR's palmitoylation.
153
The interaction of the retromer component SNX1 with Hrs may pro-
vide a molecular switch rerouting retromer cargoes to late endosomes/lyso-
somes for degradation.
120
This articulation between two trafficking routes
observed for retromer cargoes is reminiscent of the dual fate of
b
2
-adrenergic
receptor depending on the recruited scaffold,
b
-arrestin or ARRDC.
A functional kinship of RGP1 with the members of the arrestin clan
described above is even more elusive as RGP1 is a component of a dimeric
GEF with a regulatory function on the GARPmultimeric complex involved
in vesicle tethering at the TGN.
6. CONCLUSION AND PERSPECTIVES
Arrestin-fold proteins (true arrestins, human ARRDCs, ARTs,
amoebal ADCs, VPS26, RGP1) share a convergent structure with two
domains of antiparallel
b
-sheets oriented to optimally scaffold proteins in
sorting/targeting events during membrane trafficking.
Members of the arrestin clan are clearly related,
from a structural
point of view and because of
their functions
in trafficking steps of
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