Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis
Abstract 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...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56171-8 |
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| author | Chen Wang Cheng Ma Yuanyou Xu Shenghai Chang Hangjun Wu Chunlan Yan Jinghua Chen Yongping Wu Shaoya An Jiaqi Xu Qin Han Yujie Jiang Zhinong Jiang Xiakun Chu Haichun Gao Xing Zhang Yunjie Chang |
| author_facet | Chen Wang Cheng Ma Yuanyou Xu Shenghai Chang Hangjun Wu Chunlan Yan Jinghua Chen Yongping Wu Shaoya An Jiaqi Xu Qin Han Yujie Jiang Zhinong Jiang Xiakun Chu Haichun Gao Xing Zhang Yunjie Chang |
| author_sort | Chen Wang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-f2313de0377047058bebe39bf12e12a5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f2313de0377047058bebe39bf12e12a52025-01-26T12:40:36ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56171-8Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysisChen Wang0Cheng Ma1Yuanyou Xu2Shenghai Chang3Hangjun Wu4Chunlan Yan5Jinghua Chen6Yongping Wu7Shaoya An8Jiaqi Xu9Qin Han10Yujie Jiang11Zhinong Jiang12Xiakun Chu13Haichun Gao14Xing Zhang15Yunjie Chang16Department of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineProtein Facility, Core Facilities, Zhejiang University School of MedicineInstitute of Microbiology, College of Life Sciences, Zhejiang UniversityDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineInstitute of Microbiology, College of Life Sciences, Zhejiang UniversityCollege of Veterinary Medicine, College of Animal Science and Technology, Zhejiang A&F UniversityDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineCenter of Cryo-Electron Microscopy, Zhejiang University School of MedicineDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineAdvanced Materials Thrust, The Hong Kong University of Science and Technology (Guangzhou)Institute of Microbiology, College of Life Sciences, Zhejiang UniversityDepartment of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of MedicineCenter of Cryo-Electron Microscopy, Zhejiang University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-56171-8 |
| spellingShingle | Chen Wang Cheng Ma Yuanyou Xu Shenghai Chang Hangjun Wu Chunlan Yan Jinghua Chen Yongping Wu Shaoya An Jiaqi Xu Qin Han Yujie Jiang Zhinong Jiang Xiakun Chu Haichun Gao Xing Zhang Yunjie Chang Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis Nature Communications |
| title | Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis |
| title_full | Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis |
| title_fullStr | Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis |
| title_full_unstemmed | Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis |
| title_short | Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis |
| title_sort | dynamics of the mammalian pyruvate dehydrogenase complex revealed by in situ structural analysis |
| url | https://doi.org/10.1038/s41467-025-56171-8 |
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