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The initial function described for arrestins, their steric interference with
G-proteins activated by their cognate GPCRs and attenuation of their sig-
naling, is a characteristic that will not be found for the other members of the
arrestin clan that regulate other classes of cargoes. It is now known that
b
-arrestins also interact with and desensitize PM transporters and receptors
not coupled to G proteins, for example, NHE5 and insulin-like growth fac-
tor I receptor.
36,38,144
The second hallmark of arrestin-mediated receptor desensitization is the
arrestin-mediated internalization of cargoes on endocytic vesicles. Down-
regulation of stimulated PM proteins is also observed for some ARTS
and ARRDCs and clearly constitutes a point of convergence between
b
-arrestins and
a
-arrestins. However, the intimate interaction process based
on the recognition by
b
-arrestins of phosphorylated serines/threonines of
the GPCR, the disruption of a polar core, and the unfolding of the
C-terminal tail preliminary to the scaffolding of the endocytosis machinery
is not described for ARTs and ARRDCs. How cargoes regulated by
a
-arrestins are internalized still awaits extensive characterization.
The Alvarez split into
a
-arrestins and visual/
b
-arrestins is based on the
existence of [L,P]PxY motifs within the C-terminal tail of
a
-arrestins that
are able to bind the WW domains of HECT-type E3 ubiquitin ligases of
the Nedd4 family, motifs that are absent in
b
-arrestins.
130
ARTs are used
to scaffold E3 ubiquitin ligases for the ubiquitination of their cognate part-
ner. In the process, they are themselves ubiquitinated and they regulate the
endocytosis of ubiquitinated PM receptors.
10,85,87,89
Many yeast transporters
of diverse types are delivered to the vacuole once internalized in an
ART-dependent process.
89
Human ARRDC3 is similarly involved in
the degradation pathway of
b
-integrins, with ubiquitination governing
the commitment to this degradation itinerary.
81
Interestingly, members of the
b
-arrestin subfamily also bind ubiquitin E3
ligases including Nedd4.
b
-Arrestin 2 is first ubiquitinated by the RING-
type E3 ligase Mdm2, a modification that increases its affinity for the
b
2
-adrenergic receptor. Ubiquitinated
b
-arrestin 2 acts then as a scaffold
for the binding of Nedd4, which mediates receptor ubiquitination. The
interaction between
b
-arrestin 2 and Nedd4 occurs in the absence of PY
motifs on
b
-arrestin 2 and does not require the WW domains of Nedd4.
145
The difference between
a
- and
b
-arrestins does not lie in the interaction
with E3 ubiquitin ligases, but rather in the mechanism that governs this
interaction, mediated by PY motifs in
a
-arrestins binding WW domains
and yet unknown in the case of
b
-arrestins.
146
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