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Abstract
Interphotoreceptor retinoid-binding protein (IRBP) has a remarkable role in targeting
and protecting all-trans and 11-cis retinol, and 11-cis retinal during the rod and
cone visual cycles. Little is known about how the correct retinoid is efficiently
delivered and removed from the correct cell at the required time. It has been proposed
that different fatty composition at that the outer-segments and retinal-pigmented
epithelium have an important role is regulating the delivery and uptake of the visual
cycle retinoids at the cell-interphotoreceptor-matrix interface. Although this suggests
intriguing mechanisms for the role of local fatty acids in visual-cycle retinoid trafficking,
nothing is known about the structural basis of IRBP-fatty acid interactions. Such
regulation may be mediated through IRBP's unusual repeating homologous modules, each
containing about 300 amino acids. We have been investigating structure-function relationships
of Zebrafish IRBP (zIRBP), which has only two tandem modules (z1 and z2), as a model
for the more complex four-module mammalian IRBP's. Here we report the first X-ray
crystal structure of a teleost IRBP, and the only structure with a bound ligand. The
X-ray structure of z1, determined at 1.90 Å resolution, reveals a two-domain organization
of the module (domains A and B). A deep hydrophobic pocket with a single bound molecule
of oleic acid was identified within the N-terminal domain A. In fluorescence titrations
assays, oleic acid displaced all-trans retinol from zIRBP. Our study, which provides
the first structure of an IRBP with bound ligand, supports a potential role for fatty
acids in regulating retinoid binding.