Li Yang, Chen Zhi-Peng, Xu Da, Wang Liang, Cheng Meng-Ting, Zhou Cong-Zhao, Chen Yuxing, Hou Wen-Tao
Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, Anhui, China.
Cell Discov. 2024 Sep 3;10(1):92. doi: 10.1038/s41421-024-00722-8.
Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.
人类 ABC 转运蛋白 ABCD1 - 3 均定位于过氧化物酶体膜上，并参与脂酰辅酶 A 的β氧化，但它们在底物特异性方面存在差异。从胞质溶胶到过氧化物酶体的支链脂肪酸转运由 ABCD3 特异性驱动，其功能障碍会导致严重的肝脏疾病，如肝脾肿大。在此，我们报告了分别以 2.9 Å 和 3.2 Å 的分辨率解析的与植烷酰辅酶 A 和 ATP 结合的 ABCD3 的两个低温电子显微镜（cryo - EM）结构。在 ABCD3 中观察到一对植烷酰辅酶 A 分子，每个分子与一个跨膜结构域（TMD）结合，这与我们之前报道的 ABCD1 的结构不同，在 ABCD1 中每个脂酰辅酶 A 分子强烈交联两个 TMD。ATP 结合后，ABCD3 呈现出一种朝向过氧化物酶体基质开放的构象，在转运腔中留下对应于两个辅酶 A 分子的两个额外密度。结构分析与底物刺激的 ATP 酶活性测定相结合表明，当前结构可能代表 ABCD3 在转运循环中的两种状态。这些发现推进了我们对脂肪酸氧化以及相关疾病分子病理学的理解。
