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Department of Biochemistry and Molecular Pharmacology, Kimmel
Cancer Institute, Thomas Jefferson University, Philadelphia,
Pennsylvania 19107
Arrestin plays an important role in quenching phototransduction via its
ability to interact specifically with the phosphorylated light-activated form of the visual receptor rhodopsin (P-Rh*). Previous
studies have demonstrated that Arg175 in bovine arrestin is directly
involved in the phosphorylation-dependent binding of arrestin to
rhodopsin and seems to function as a phosphorylation-sensitive trigger.
In this study, we further probed the molecular mechanism of
phosphorylation recognition by substituting 19 different amino acids
for Arg175. We also assessed the effects of mutagenesis of several
other highly conserved residues within the phosphorylation-recognition region (Val170, Leu172, Leu173, Ile174, Val177, and Gln178). The binding of all of these mutants to P-Rh*, light-activated rhodopsin, and truncated rhodopsin, which lacks the carboxyl-terminal
phosphorylation sites, was then characterized. Overall, our results
suggest that arrestin interaction with the phosphorylated
carboxyl-terminal domain of rhodopsin activates two relatively
independent changes in arrestin: (a) mobilization of additional binding
sites and (b) increased affinity of the phosphorylation-recognition
region for the rhodopsin carboxyl-terminal domain. Together, these two mechanisms ensure the exquisite selectivity of arrestin toward P-Rh*.
Mutagenesis of residues that play a major role in binding site
mobilization and phosphorylation-recognition enabled us to create
"constitutively active" (phosphorylation-independent) arrestin mutants that have high affinity for both P-Rh* and light-activated rhodopsin. The introduction of a negative charge in position 175 was
particularly effective in this respect. A detailed molecular model of
phosphorylation-recognition is proposed.
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