Arrestins and Protein Ubiquitination - Progress in Molecular Biology and Translational Science - page 190

6.2. Saccharomyces cerevisiae
In the yeast S. cerevisiae , ubiquitination of plasma membrane proteins serves
as the major signal for their endocytosis. 102 In yeast, ubiquitination of plasma
membrane substrates is mediated by the HECT domain E3 ubiquitin ligase,
Rsp5 (a homolog of mammalian Nedd4) but most yeast membrane proteins
do not contain a polyproline motif, which is a major recognition domain for
binding with the WW domains in Rsp5. The conundrum of how Rsp5 can
recognize and modify these substrates was recently resolved by studies that
uncovered the existence of a family of 10 adaptor proteins called arrestin-
related trafficking adaptors (ARTs 1-10) that carry polyproline motifs that
bind to the WW domains in Rsp5. 103-106 Although ARTs do not share
sequence homology with mammalian arrestins, structural modeling predicts
that they fold into three-dimensional configurations carrying the character-
istic amino and C-terminal arrestin domain architecture. ARTs function as
E3 ubiquitin ligase adaptors for various yeast plasma membrane transporters:
ART1 (also known as Cvs7 or Ldb19) for methionine transporter Mup1 and
arginine transporter Can1; ART3 (also known as Aly2) for dicarboxylic acid
transporter Dip5; ARTs 1 and 2 (ART2 is also termed Ecm21) for lysine
transporter Lyp1; ARTs 2 and 8 (ART8 is also termed Csr2) for the man-
ganese transporter Smf1; ART5 for the inositol transporter Itr1; and ART4
(ART4 is also termed Rod1); and ART8 for the high-affinity hexose trans-
porter Hxt6. In addition to these ARTs, yeast express other proteins with
partial or no conservation of arrestin domain sequences, but which contain
polyproline motifs and are substrates or adaptors for Rsp5. 71 ART9 (also
called Rim8 and related to PalF of A. nidulans discussed above) is a unique
member in having arrestin domains but no polyproline motifs. ART9
deletion proves to have a harsher effect on yeast growth than a combined
deletion of all the other ARTs. 105 Although more partners for these
ART adaptors are emerging, their role in the regulation of yeast 7TMRs
Ste2 and Ste3 remains to be documented.
6.3. Mammalian arrestin domain-containing proteins
The three-dimensional X-ray crystal structure of VPS26, which is a subunit
of the mammalian retromer complex, shows an unprecedented resemblance
to that of arrestin(s), although there is no sequence conservation between the
two proteins. 107,108 Previous structure-function studies of mammalian
arrestins support the idea that these molecules exist in a basal rigid confor-
mation due to the restrictions imposed by the polar amino acid interactions