caa a22 4500 463208331 CHVBK 20180405153132.0 cr unu---uuuuu 170326e20071201xx s 000 0 eng 10.1007/s10863-007-9118-6 doi (NATIONALLICENCE)springer-10.1007/s10863-007-9118-6 Molday Robert Department of Biochemistry & Molecular Biology, Centre for Macular Research, University of British Columbia, 2350 Health Sciences Mall, V6T 1Z3, Vancouver, BC, Canada aut ATP-binding cassette transporter ABCA4: Molecular properties and role in vision and macular degeneration [Elektronische Daten] [Robert Molday] ABCA4, also known as ABCR or the rim protein, is a member of the ABCA subfamily of ATP binding cassette (ABC) transporters expressed in vertebrate rod and cone photoreceptor cells and localized to outer segment disk membranes. ABCA4 is organized in two tandem halves, each consisting of a transmembrane segment followed successively by a large exocytoplasmic domain, a multispanning membrane domain, and a nucleotide-binding domain. Over 400 mutations in ABCA4 have been linked to Stargardt macular degeneration and related retinal degenerative diseases that cause severe vision loss in affected individuals. Direct binding studies and ATPase activation measurements have identified N-retinylidene-phosphatidylethanolamine, a product generated from the photobleaching of rhodopsin, as the substrate for ABCA4. Mice deficient in ABCA4 accumulate phosphatidylethanolamine, all-trans retinal, and N-retinylidene-phosphatidylethanolamine in photoreceptors and the diretinal pyridinium compound A2E in retinal pigment epithelial cells. On the basis of these studies, ABCA4 is proposed to actively transport or flip N-retinylidene-phosphatidylethanolamine from the lumen to the cytoplasmic side of disc membranes following the photobleaching of rhodopsin. This transport activity insures that retinoids do not accumulate in disc membranes. Disease-linked mutations in ABCA4 that result in diminished transport activity lead to an accumulation of all-trans retinal and N-retinylidene-PE in disc membranes which react to produce A2E precursors. A2E progressively accumulates as lipofuscin deposits in retinal pigment epithelial cells as a result of phagocytosis of outer segment discs. A2E and photo-oxidation products cause RPE cell death and consequently photoreceptor degeneration resulting in a loss in vision in individuals with Stargardt macular degeneration and other retinal degenerative diseases associated with mutations in ABCA4. Springer Science+Business Media, LLC, 2007 Transporter nationallicence Photoreceptors nationallicence Stargardt macular degeneration nationallicence Disease mechanisms nationallicence ABC transporters nationallicence Journal of Bioenergetics and Biomembranes Springer US; http://www.springer-ny.com 39/5-6(2007-12-01), 507-517 0145-479X 39:5-6<507 2007 39 10863 https://doi.org/10.1007/s10863-007-9118-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10863-007-9118-6 text/html Onlinezugriff via DOI NATIONALLICENCE 100 1- Molday Robert Department of Biochemistry & Molecular Biology, Centre for Macular Research, University of British Columbia, 2350 Health Sciences Mall, V6T 1Z3, Vancouver, BC, Canada aut NATIONALLICENCE 773 0- Journal of Bioenergetics and Biomembranes Springer US; http://www.springer-ny.com 39/5-6(2007-12-01), 507-517 0145-479X 39:5-6<507 2007 39 10863 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer