ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) transporters that is preferentially localized along the rim region of rod and cone photoreceptor outer segment disc membranes. It uses the energy from ATP binding and hydrolysis to transport N-retinylidene-phosphatidylethanolamine (N-Ret-PE), the Schiff base adduct of retinal and phosphatidylethanolamine, from the lumen to the cytoplasmic leaflet of disc membranes. This ensures that all-trans-retinal and excess 11-cis-retinal are efficiently cleared from photoreceptor cells thereby preventing the accumulation of toxic retinoid compounds. Loss-of-function mutations in the gene encoding ABCA4 cause autosomal recessive Stargardt macular degeneration, also known as Stargardt disease (STGD1), and related autosomal recessive retinopathies characterized by impaired central vision and an accumulation of lipofuscin and bis-retinoid compounds. High resolution structures of ABCA4 in its substrate and nucleotide free state and containing bound N-Ret-PE or ATP have been determined by cryo-electron microscopy providing insight into the molecular architecture of ABCA4 and mechanisms underlying substrate recognition and conformational changes induced by ATP binding. The expression and functional characterization of a large number of disease-causing missense ABCA4 variants have been determined. These studies have shed light into the molecular mechanisms underlying Stargardt disease and a classification that reliably predicts the effect of a specific missense mutation on the severity of the disease. They also provide a framework for developing rational therapeutic treatments for ABCA4-associated diseases.

ABCA4 是 ATP 结合盒 (ABC) 转运蛋白超家族的成员，该转运蛋白优先位于视杆和视锥细胞外段圆盘膜的边缘区域。它利用 ATP 结合和水解产生的能量将N-视黄亚基-磷脂酰乙醇胺 ( N -Ret-PE)（视黄醛和磷脂酰乙醇胺的席夫碱加合物）从内腔运输到椎间盘膜的细胞质小叶。这确保了全反式视网膜和过量的 11-顺式-视网膜从感光细胞中有效清除，从而防止有毒类维生素A化合物的积累。编码 ABCA4 的基因功能丧失突变导致常染色体隐性遗传性 Stargardt 黄斑变性，也称为 Stargardt 病 (STGD1)，以及相关的常染色体隐性遗传性视网膜病，其特征是中心视力受损和脂褐质和双维甲酸化合物的积累。ABCA4 在其底物和核苷酸游离状态下的高分辨率结构，并含有结合的N-Ret-PE 或 ATP 已通过低温电子显微镜测定，从而深入了解 ABCA4 的分子结构以及底物识别和由 ATP 结合诱导的构象变化的机制。已经确定了大量致病错义 ABCA4 变体的表达和功能表征。这些研究揭示了斯塔加特病的分子机制以及可靠预测特定错义突变对疾病严重程度影响的分类。它们还为开发 ABCA4 相关疾病的合理治疗方法提供了框架。