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may act as coreceptors for coincidence detection, increasing the binding
affinity/selectivity of activated arrestins for a phosphorylated GPCR. Muta-
tions in arrestin's phosphoinositide-binding site impair
b
2
-adrenergic recep-
tor endocytosis.
76
2.6. Conservation analysis of essential residues among visual
and
-arrestins
Analysis of amino acid conservation among proteins from the same family
highlights the importance of each position for the protein's structure or
function. If the amino acid conservation of visual arrestins/
b
-arrestins par-
alogues in several species (human, fly, worm,
Ciona
) is scored on the online
Consurf server,
46,47
a very strong consensus is obtained for all amino acids
involved in the polar core and the electrostatic interaction domain (
Fig. 2.1
),
evidencing the mechanism of receptor recognition and binding already pre-
sent in the oldest arrestin forms (
Ciona
) and conserved through evolution.
And, as expected from the very different cognate receptors, the remaining
of the molecule is weakly conserved in terms of amino acid identity.
b
3. NOVEL ARRESTIN-RELATED PROTEINS
Recently, novel arrestin-related proteins have been found in the
genomes from protists to mammals. All these proteins harbor an arrestin
core, with both arrestin N- and C-domains.
However, this arrestin core is extended, in some cases, on both extrem-
ities by sequence appendages likely to provide novel specificities for partner
interactions or function.
3.1. Mammalian ARRDCs
Besides the true arrestins, the genome from mammals encodes six proteins
containing the arrestin N- and C-domains: ARRDC1-5 and TXNIP
(thioredoxin-interacting protein) also known as VDUP (vitamin D3
upregulated protein). Interestingly, paralogues for ARRDCs and TXNIP
can be found in the crown of higher eukaryotes outside mammals, namely,
fish, frog, and bird. Fly and worm harbor an ARRDC5 paralogue only.
No crystal structure of ARRDCs has been solved so far, although
a preliminary X-ray analysis has been conducted on TXNIP
crystals.
77, Note added in Proof
At the date of submission of this review, the
structure of TXNIP-TRX complex has been deposited at the PDB by
Hwang and Kim but has not yet been released. We have modeled the
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