The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to cellular fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive nervous system demyelination, and neurological impairments including the potentially fatal disease X-linked adrenoleukodystrophy (X-ALD). Molecular details underlying substrate recognition and transport by ABCD1 are poorly understood. Here we determined cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution that reveal key details of its transmembrane cavity and ATP dependent conformational transitions. We identify structural elements distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Together, our data support a transport mechanism where only the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane cavity while the acyl chains extend out into the surrounding membrane bilayer, help rationalize disease causing mutations, and provide a framework for ABCD1 targeted structure-based drug design.

中文翻译：

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脂质环境中人过氧化物酶体脂肪酸转运蛋白 ABCD1 的结构

过氧化物酶体超长链脂肪酸 (VLCFA) 转运蛋白 ABCD1 是细胞脂肪酸分解代谢和脂质生物合成的核心。其功能障碍是 VLCFA 的有毒细胞溶质积累、进行性神经系统脱髓鞘和神经损伤的基础，包括可能致命的 X 连锁肾上腺脑白质营养不良 (X-ALD)。ABCD1 底物识别和运输的分子细节知之甚少。在这里，我们确定了磷脂纳米盘中 ABCD1 的冷冻电镜结构，其核苷酸结合构象对过氧化物酶体腔开放，向内构象以高达 3.5 Å 的分辨率向细胞质开放，揭示了其跨膜腔和 ATP 依赖性构象转换的关键细节. 我们确定了将 ABCD1 与其最接近的同源物区分开来的结构元件，并表明 VLCFA 的辅酶 A (CoA) 酯以物种依赖性方式调节 ABCD1 活性。总之，我们的数据支持一种运输机制，其中只有 VLCFA-CoA 的 CoA 部分进入亲水性跨膜腔，而酰基链延伸到周围的膜双层中，有助于使引起疾病的突变合理化，并为基于 ABCD1 靶向结构的结构提供框架药物设计。