The retinal ATP binding cassette (ABC) transporter, ABCR, is linked to several inherited visual disease syndromes; including Stargardt disease, cone-rod dystrophy, fundus flavimacultitis and age related macular degeneration (ARMD). An overview of genetic analyses clearly demonstrate that missense amino acid substitutions occur with equal frequency in conserved domains, as well as non-conserved domains throughout the whole of the ABCR gene. Our overall aim is to investigate the mechanism of action of ABCR protein and how genetic mutations observed in Stargardt disease and ARMD influence energy transduction in retinal transport so that new and more precise therapies may be developed in the future. ? ? (1) We are carrying out a detailed structure-function analysis of nucleotide binding and hydrolysis by ABCR. We plan to test the hypothesis that certain mutations observed in Stargardt disease and ARMD lead to conformational changes which in turn influence nucleotide binding and hydrolysis. This will help us to develop a predictive model for the likely effect of a given mutation on the enzymatic activity and associated structural changes in ABCR. (2) Analyze extracellular domain mutations in substrate (retinal) binding. In this specific aim we address, what are the biochemical consequences of extracellular domain mutations in ABCR function. We will approach this important question from several directions. We will investigate (a) identification of ECD mutations that lead to a loss of retinal stimulation of ATPase; (b) retinal binding by recombinant ECD polypeptides. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15EY013113-02
Application #
6668082
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Dudley, Peter A
Project Start
2000-07-01
Project End
2007-03-31
Budget Start
2003-07-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$157,000
Indirect Cost
Name
Thomas Jefferson University
Department
Biostatistics & Other Math Sci
Type
Schools of Allied Health Profes
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Wangtiraumnuay, Nutsuchar; Capasso, Jenina; Tsukikawa, Mai et al. (2018) Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing. Eur J Ophthalmol 28:123-126
Biswas-Fiss, Esther E; Affet, Stephanie; Ha, Malissa et al. (2012) Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4. J Biol Chem 287:44097-107
Biswas-Fiss, Esther E; Kurpad, Deepa S; Joshi, Kinjalben et al. (2010) Interaction of extracellular domain 2 of the human retina-specific ATP-binding cassette transporter (ABCA4) with all-trans-retinal. J Biol Chem 285:19372-83
Biswas-Fiss, Esther E (2006) Interaction of the nucleotide binding domains and regulation of the ATPase activity of the human retina specific ABC transporter, ABCR. Biochemistry 45:3813-23
Biswas-Fiss, Esther E (2003) Functional analysis of genetic mutations in nucleotide binding domain 2 of the human retina specific ABC transporter. Biochemistry 42:10683-96
Suarez, Tatiana; Biswas, Subhasis B; Biswas, Esther E (2002) Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration. J Biol Chem 277:21759-67
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Biswas, E E; Biswas, S B (2000) The C-terminal nucleotide binding domain of the human retinal ABCR protein is an adenosine triphosphatase. Biochemistry 39:15879-86