Arrestins and Protein Ubiquitination - Progress in Molecular Biology and Translational Science - page 179

C

Agonist

Class A, 2 AR

P P

GRKs

Stable receptor-

P P

arrestin-Ub complex,

Endosome

Sustained pERK
on endosomes

-Arrestin Ub

P
P

D

Agonist

P

Class B, V 2 R

P
P

P
P

GRKs

Transient receptor-
arrestin complex,
No pERK on endosomes

Endosome

No ubiquitination

-Arrestin-0K

-Arrestin-0K

Figure 7.3 Cont'd (C) A b-arrestin2-Ub chimera, which cannot be deubiquitinated,
forms a stable complex with the class A b 2 AR and scaffolds active ERK on endosomes.
(D) The mutant b-arrestin2-0K that lacks ubiquitination sites forms a highly unstable
complex even with a class B receptor.

support the idea that the b -arrestin-binding pattern, as well as the stability
and signaling of receptor- b -arrestin complexes, is dictated by the molecular
signatures on the receptor carboxyl terminus as well as on b -arrestins,
namely, distinct phosphorylation motifs corresponding to either class A or
class B receptors, and ubiquitin chains on b -arrestin. The 7TMR recycling
and resensitization kinetics can be further dictated by ubiquitination of the
receptor itself.
Ubiquitination occurs on the e -amino group of lysine residues, and there
is no consensus sequence for substrate ubiquitination. Both b -arrestin
isoforms have many lysines (e.g., 35 in rat b -arrestin1 and 31 in rat
b -arrestin2) dispersed along the length of the protein which presents a chal-
lenging task to identify specific lysines targeted for ubiquitination.
By undertaking series of mutagenesis steps, the lysine residues in b -arrestin2
targeted for stable ubiquitination as induced by the class B type AT 1a R have
been mapped; here, the stable ubiquitination occurs primarily at the vicinal
lysines 11 and 12 in rat b -arrestin2. 56 Mutation of these lysines to arginines