Article ; Online: Retinal-phospholipid Schiff-base conjugates and their interaction with ABCA4, the ABC transporter associated with Stargardt disease.
The Journal of biological chemistry
2023 Volume 299, Issue 5, Page(s) 104614
Abstract: N-retinylidene-phosphatidylethanolamine (N-Ret-PE), the Schiff-base conjugate formed through the reversible reaction of retinal (Vitamin A-aldehyde) and phosphatidylethanolamine, plays a crucial role in the visual cycle and visual pigment ... ...
Abstract | N-retinylidene-phosphatidylethanolamine (N-Ret-PE), the Schiff-base conjugate formed through the reversible reaction of retinal (Vitamin A-aldehyde) and phosphatidylethanolamine, plays a crucial role in the visual cycle and visual pigment photoregeneration. However, N-Ret-PE can react with another molecule of retinal to form toxic di-retinoids if not removed from photoreceptors through its transport across photoreceptor membranes by the ATP-binding-cassette transporter ABCA4. Loss-of-function mutations in ABCA4 are known to cause Stargardt disease (STGD1), an inherited retinal degenerative disease associated with the accumulation of fluorescent di-retinoids and severe loss in vision. A larger assessment of retinal-phospholipid Schiff-base conjugates in photoreceptors is needed, along with further investigation of ABCA4 residues important for N-Ret-PE binding. In this study we show that N-Ret-PE formation is dependent on pH and phospholipid content. When retinal is added to liposomes or photoreceptor membranes, 40 to 60% is converted to N-Ret-PE at physiological pH. Phosphatidylserine and taurine also react with retinal to form N-retinylidene-phosphatidylserine and N-retinylidene-taurine, respectively, but at significantly lower levels. N-retinylidene-phosphatidylserine is not a substrate for ABCA4 and reacts poorly with retinal to form di-retinoids. Additionally, amino acid residues within the binding pocket of ABCA4 that contribute to its interaction with N-Ret-PE were identified and characterized using site-directed mutagenesis together with functional and binding assays. Substitution of arginine residues and hydrophobic residues with alanine or residues implicated in STGD1 significantly reduced or eliminated substrate-activated ATPase activity and substrate binding. Collectively, this study provides important insight into conditions which affect retinal-phospholipid Schiff-base formation and mechanisms underlying the pathogenesis of STGD1. |
---|---|
MeSH term(s) | Humans ; ATP-Binding Cassette Transporters/metabolism ; Phosphatidylserines ; Phospholipids ; Retinoids/metabolism ; Stargardt Disease/metabolism |
Chemical Substances | ABCA4 protein, human ; ATP-Binding Cassette Transporters ; N-retinylidene-phosphatidylethanolamine ; Phosphatidylserines ; Phospholipids ; Retinoids |
Language | English |
Publishing date | 2023-03-16 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2997-x |
ISSN | 1083-351X ; 0021-9258 |
ISSN (online) | 1083-351X |
ISSN | 0021-9258 |
DOI | 10.1016/j.jbc.2023.104614 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
Uc I Zs.108: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.