School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
Nat Commun. 2022 Jun 8;13(1):3299. doi: 10.1038/s41467-022-30974-5.
Human ABC transporter ABCD1 transports very long-chain fatty acids from cytosol to peroxisome for β-oxidation, dysfunction of which usually causes the X-linked adrenoleukodystrophy (X-ALD). Here, we report three cryogenic electron microscopy structures of ABCD1: the apo-form, substrate- and ATP-bound forms. Distinct from what was seen in the previously reported ABC transporters, the two symmetric molecules of behenoyl coenzyme A (C22:0-CoA) cooperatively bind to the transmembrane domains (TMDs). For each C22:0-CoA, the hydrophilic 3'-phospho-ADP moiety of CoA portion inserts into one TMD, with the succeeding pantothenate and cysteamine moiety crossing the inter-domain cavity, whereas the hydrophobic fatty acyl chain extends to the opposite TMD. Structural analysis combined with biochemical assays illustrates snapshots of ABCD1-mediated substrate transport cycle. It advances our understanding on the selective oxidation of fatty acids and molecular pathology of X-ALD.
人 ABC 转运体 ABCD1 将非常长链脂肪酸从细胞质转运到过氧化物酶体进行β氧化，其功能障碍通常导致 X 连锁肾上腺脑白质营养不良（X-ALD）。在这里，我们报告了 ABCD1 的三个低温电子显微镜结构：apo 形式、底物结合和 ATP 结合形式。与先前报道的 ABC 转运体不同，两个对称的二十二碳酰辅酶 A（C22:0-CoA）分子协同结合到跨膜结构域（TMD）。对于每个 C22:0-CoA，辅酶 A 部分的亲水 3'-磷酸-ADP 部分插入一个 TMD，随后的泛酸和半胱氨酸部分穿过域间腔，而疏水性脂肪酸链延伸到相反的 TMD。结构分析结合生化分析说明了 ABCD1 介导的底物转运循环的快照。它推进了我们对脂肪酸选择性氧化和 X-ALD 分子病理学的理解。
