Molecular structures of the eukaryotic retinal importer ABCA4.
Molecular structures of the eukaryotic retinal importer ABCA4.
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作者：
Liu F;Lee J;Chen J
ATP结合盒（ABC）转运蛋白家族包含数千个具有不同功能的成员。由ATP水解提供动力的底物的运动可以是向外（输出）或向内（输入）。ABCA 4是一种真核生物转运蛋白，将视网膜转运到胞质中进入视觉循环。它还可以清除椎间盘腔中的有毒类维生素A。ABCA4突变会导致视力受损或失明。尽管经过数十年的临床、生物化学和动物模型研究，ABCA 4的分子机制仍不清楚。在这里，我们报告了两种构象的人ABCA 4的结构。在缺乏ATP的情况下，ABCA 4采取向外的构象，准备招募底物。ATP的存在诱导大的构象变化，可能导致底物释放。这些结构为理解许多致病突变提供了分子基础，并为揭示ABCA 4如何招募，翻转和释放类维生素A的新实验提供了合理的指导。
The ATP-binding cassette (ABC) transporter family contains thousands of members with diverse functions. Movement of the substrate, powered by ATP hydrolysis, can be outward (export) or inward (import). ABCA4 is a eukaryotic importer transporting retinal to the cytosol to enter the visual cycle. It also removes toxic retinoids from the disc lumen. Mutations in ABCA4 cause impaired vision or blindness. Despite decades of clinical, biochemical, and animal model studies, the molecular mechanism of ABCA4 is unknown. Here, we report the structures of human ABCA4 in two conformations. In the absence of ATP, ABCA4 adopts an outward-facing conformation, poised to recruit substrate. The presence of ATP induces large conformational changes that could lead to substrate release. These structures provide a molecular basis to understand many disease-causing mutations and a rational guide for new experiments to uncover how ABCA4 recruits, flips, and releases retinoids.