True Arrestins and Arrestin-Fold Proteins: A Structure-Based Appraisal - Progress in Molecular Biology and Translational Science - page 43

membrane-embedded proteins. The mechanisms of cargo-recognition used
by the diverse members of the arrestin clan seem clearly different, and so far
only b -arrestins are involved in the interference with G-protein signaling
and in the scaffolding of secondary signaling platforms on the endosome.
Visual/ b -arrestins, ARRDCs and ARTs are all involved in the down-
regulation of PM proteins. The initial steps of their cargo recognition are
similar ( Fig. 2.7 A and C). Both proteins are cytosolic in their phosphorylated
inactive state. Their dephosphorylation and ubiquitination are temporally
correlated with their recruitment on their cargo(es). There is, however,
no biochemical evidence that this recruitment proceeds through the same
mechanism or that it involves a polar core and the unveiling of sites for
the endocytic machinery for both adaptor proteins. The next step in the
receptor/cargo desensitization process is the recruitment by arrestins/ARTs
of an E3 ubiquitin ligase and the subsequent ubiquitination of the cargo.
Data are lacking as to the detailed internalization mechanism of PM trans-
porters by ARTs. The fate of internalized cargoes is either recycling to the
PM and resensitization or degradation in the lysosome. For some human
receptors, the choice between these two fates is dependent on the recruited
adaptor, b -arrestins or ARRDCs. In yeast, the role of ARTs is related to the
vacuolar degradation of internalized PM transporters. No data on the pos-
sible recycling of these transporters are currently available.
The retromer represents a very different intercompartmental trafficking
machinery ( Fig. 2.7 B). It is a hetero-oligomer involved in retrograde trans-
port from the endosome to the TGN of CI-MPR and other Golgi proteins.
The trigger of this back transport is, in the case of the CI-MPR, related to
the dissociation of lysosomal enzymes carried over from the TGN, but the
detailed mechanism is not yet known. The arrestin-fold protein VPS26,
along with VPS35 and VPS29, make up the trimeric cargo-recognition sub-
complex, in which the primary Golgi protein recognition subunit is VPS35.
The retromer complex is mechanistically very different from an arrestin scaf-
fold in terms of direction and regulation of the transport, recognized cargoes,
and recruited partners.
The last arrestin-fold protein described here is RGP1. It is part of a
heterodimeric Rab6 GEF at the TGN that regulates the tethering of incom-
ing endosomal vesicles involved in the retrograde transport of Golgi proteins
( Fig. 2.7 D). No functional kinship relates it to an arrestin, an ART, or even
VPS26. Its exact function awaits biochemical characterization.
A challenge for the future is the attainment of full-length crystal struc-
tures for ARTs, ARRDCs, ADCs, and RGP1. Most of these arrestin-fold