Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis
The multi-enzyme pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle and plays vital roles in metabolism, energy production, and cellular signaling. Although all components have been individually characterized, the intact PDHc structure remains unclear, hampering our understanding of its composition and dynamical catalytic mechanisms. Here, we report the in-situ architecture of intact mammalian PDHc by cryo-electron tomography. The organization of peripheral E1 and E3 components varies substantially among the observed PDHcs, with an average of 21 E1 surrounding each PDHc core, and up to 12 E3 locating primarily along the pentagonal openings. In addition, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, and the interaction interfaces were further analyzed by molecular dynamics simulations. By revealing intrinsic dynamics of PDHc peripheral compositions, our findings indicate a distinctive activity regulation mechanism, through which the number of E1, E3 and functional LDs may be coordinated to meet constantly changing demands of metabolism.
Authors
- Yunjie Chang (ORCID: https://orcid.org/0009-0006-2815-613X)
- Haichun Gao (ORCID: https://orcid.org/0000-0002-2647-6563)
- Shaoya An
- Yujie Jiang (ORCID: https://orcid.org/0009-0000-8817-6913)
- Shenghai Chang (ORCID: https://orcid.org/0000-0002-0908-711X)
- Xiakun Chu (ORCID: https://orcid.org/0000-0003-3166-7070)
- Yuanyou Xu (ORCID: https://orcid.org/0000-0001-6800-2465)
- Jiaqi Xu (ORCID: https://orcid.org/0000-0002-6735-9267)
- Chen Wang (ORCID: https://orcid.org/0009-0001-9633-8879)
- Xing Zhang (ORCID: https://orcid.org/0000-0002-6776-326X)
- Chunlan Yan
- Qin Han (ORCID: https://orcid.org/0000-0002-7317-0823)
- Jinghua Chen (ORCID: https://orcid.org/0000-0001-8122-8450)
- Yongping Wu (ORCID: https://orcid.org/0000-0002-4195-0614)
- Cheng Ma (ORCID: https://orcid.org/0000-0002-7214-4084)
- Zhinong Jiang (ORCID: https://orcid.org/0000-0003-3844-5905)
- Hangjun Wu
Institutions
- Zhejiang A & F University (CN)
- Hong Kong University of Science and Technology (HK)
- Sir Run Run Shaw Hospital (CN)
- Zhejiang University-University of Edinburgh Institute (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1038/s41467-025-56171-8
- Citations
- 10
- Primary Topic
- Biochemical Acid Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 11.12
Funders
- National Natural Science Foundation of China
- Zhejiang University
- National Key Research and Development Program of China