Evolving 40 times independently, eyes are striking examples of convergent evolution in that 11-cis retinaldehyde is always used for photon capture, yet the mechanism for its regeneration may be dramatically different in between systems. In particular, insects, cephalopods and vertebrates show varying physical separation of the cis-->trans photoisomerization and chromphore reisomerization. In the vertebrate retina, these two processes are actually distributed between different cells. This compartmentalization is made possible by the phylogenetic innovation of the two-layered optic cup of the vertebrate retina. This unprecedented design created the subretinal space as a novel anatomical compartment allowing photoreceptors access to the retinal pigment epithelium (RPE) and Müller cells, the two cell types which share the burden of 11-cis retinoid regeneration. To take advantage of this arrangement, early vertebrates appear to have recruited for retinoid binding, the betabetaalpha-spiral fold proven useful in enoyl-CoA isomerase/hydratases, and the carboxy-terminal proteases for stabilizing hydrophobic ligands. Quadruplication of this functional domain within a single polypeptide lead to the emergence of interphotoreceptor retinoid-binding protein (IRBP). IRBP is the main soluble component of the IPM, and is prevented from diffusing out of the subretinal space because its large size excludes it from the photoreceptor/Müller cell zonulae adheretes. Despite this physical entrapment, IRBP is rapidly turned over within the IPM through a process that coordinates secretion of the protein by the photoreceptors, and its removal from the matrix by RPE and photoreceptor endocytosis. The present review will summarize what is known about the structure and function of IRBP to anticipate future avenues of research.

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Interphotoreceptor retinoid binding protein (IRBP), the major soluble component of the interphotoreceptor matrix, is critical to the function, integrity, and development of the vertebrate retina. Although its role is poorly understood, IRBP has been thought to protect 11-cis retinal and all-trans retinol while facilitating their exchange between the photoreceptors and retinal-pigmented epithelium. We determined the X-ray structure of one of the functional units, or modules, of Xenopus laevis IRBP to 1.8 A resolution by multiwavelength anomalous dispersion. The monomeric protein consists of two domains separated by a hydrophobic ligand binding site. A structural homology to the recently solved photosystem II D1 C-terminal-processing protease and the enoyl-CoA isomerase/hydratase family suggests the utility of a common fold used in diverse settings, ranging from proteolysis to fatty acid isomerization to retinoid transport.

PURPOSE Interphotoreceptor retinoid-binding protein (IRBP) has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. This study was performed to determine whether mutations in the IRBP gene (RBP3) are associated with photoreceptor degeneration. METHODS A consanguineous family was ascertained in which four children had autosomal recessive retinitis pigmentosa (RP). Homozygosity mapping performed with SNP microarrays revealed only one homozygous region shared by all four affected siblings. Sequencing of RBP3, contained in this region, was performed in this family and others with recessive RP. Screening was also performed on patients with various other forms of retinal degeneration or malfunction. RESULTS Sequence analysis of RBP3 revealed a homozygous missense mutation (p.Asp1080Asn) in the four affected siblings. The mutation affects a residue that is completely conserved in all four homologous modules of the IRBP protein of vertebrate species and in C-terminal-processing proteases, photosynthesis enzymes found in bacteria, algae, and plants. Based on the previously reported crystal structure of Xenopus IRBP, the authors predict that the Asp1080-mediated conserved salt bridge that appears to participate in scaffolding of the retinol-binding domain is abolished by the mutation. No RBP3 mutations were detected in 395 unrelated patients with recessive or isolate RP or in 680 patients with other forms of hereditary retinal degeneration. CONCLUSIONS Mutations in RBP3 are an infrequent cause of autosomal recessive RP. The mutation Asp1080Asn may alter the conformation of the IRBP protein by disrupting a conserved salt bridge.

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