Architecture of intact mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis

作者：Chen Wang, Cheng Ma, Shenghai Chang, Hangjun Wu, Chunlan Yan, Jinghua Chen, Yongping Wu, Shaoya An, Jiaqi Xu, Qin Han, Yujie Jiang, Zhinong Jiang, Haichun Gao, Xing Zhang, Yunjie Chang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.02.01.578502 · 被引用次数：1 · 研究领域：Biochemical Acid Research Studies、Metabolism and Genetic Disorders、Mitochondrial Function and Pathology

The multi-enzyme pyruvate dehydrogenase complex (PDC) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A and is essential for cellular energy metabolism. Although individual components have been characterized, the structure of intact PDC remains unclear, hampering our understanding of its composition and multi-step catalytic reactions. Here, we report the in-situ architecture of intact PDC within mammalian mitochondria by cryo-electron tomography. The organization of peripheral E1 and E3 multimers varies substantially among PDCs. We discovered 1-46 E1 heterotetramers surrounding each PDC core, and up to 12 E3 dimers locating primarily along the pentagonal openings. Furthermore, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, implicating the mechanism of substrate channeling. Our findings reveal the intrinsic dynamics of PDC peripheral compositions, suggesting an additional model in which the number of assembled E1 heterotetramer, E3 dimer, and functional LDs of PDC may be regulated to further control its catalytic activity.