title: Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4.
abstract: The retina-specific ATP binding cassette transporter, ABCA4 protein, is associated with a broad range of inherited macular degenerations, including Stargardt disease, autosomal recessive cone rod dystrophy, and fundus flavimaculatus. In order to understand its role in retinal transport in rod out segment discs, we have investigated the interactions of the soluble domains of ABCA4 with both 11-cis- and all-trans-retinal. Using fluorescence anisotropy-based binding analysis and recombinant polypeptides derived from the amino acid sequences of the four soluble domains of ABCA4, we demonstrated that the nucleotide binding domain 1 (NBD1) specifically bound 11-cis-retinal. Its affinity for all-trans-retinal was markedly reduced. Stargardt disease-associated mutations in this domain resulted in attenuation of 11-cis-retinal binding. Significant differences in 11-cis-retinal binding affinities were observed between NBD1 and other cytoplasmic and lumenal domains of ABCA4. The results suggest a possible role of ABCA4 and, in particular, the NBD1 domain in 11-cis-retinal binding. These results also correlate well with a recent report on the in vivo role of ABCA4 in 11-cis-retinal transport.
authors.affiliation: Department of Bioscience Technologies, Program in Biotechnology, Jefferson School of Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Esther.Biswas@jefferson.edu
authors.forename: Esther E
authors.initials: EE
authors.lastname: Biswas-Fiss
authors.forename: Stephanie
authors.initials: S
authors.lastname: Affet
authors.forename: Malissa
authors.initials: M
authors.lastname: Ha
authors.forename: Subhasis B
authors.initials: SB
authors.lastname: Biswas
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D009711:Nucleotides; D012176:Retinoids; D000255:Adenosine Triphosphate