Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-09-03 DOI:10.1038/s41421-024-00722-8
Yang Li, Zhi-Peng Chen, Da Xu, Liang Wang, Meng-Ting Cheng, Cong-Zhao Zhou, Yuxing Chen, Wen-Tao Hou
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Abstract

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.

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人类 ABCD3 介导的过氧物酶体酰基-CoA 转运的结构性启示。
人类 ABC 转运体 ABCD1-3 都定位于过氧物酶体膜上,参与脂肪酰基-CoAs 的β-氧化,但它们在底物特异性上有所不同。支链脂肪酸从细胞质到过氧物酶体的转运是由 ABCD3 特别驱动的,ABCD3 的功能障碍会导致严重的肝病,如肝脾肿大。在这里,我们报告了 ABCD3 与植烷酰-CoA 和 ATP 结合的两个低温电子显微镜(cryo-EM)结构,分辨率分别为 2.9 Å 和 3.2 Å。在 ABCD3 中观察到一对植物酰基-CoA 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 结构不同,在 ABCD1 中,每个脂肪酰基-CoA 分子与两个跨膜结构域强烈交联。与 ATP 结合后,ABCD3 呈现出一种向过氧物酶体基质开放的构象,留下两个额外的密度,对应于深深嵌入转运腔的两个 CoA 分子。结构分析与底物刺激 ATPase 活性测定相结合表明,目前的结构可能代表了 ABCD3 在转运循环中的两种状态。这些发现加深了我们对脂肪酸氧化及相关疾病分子病理学的理解。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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