Molecular architecture of the mammalian 2-oxoglutarate dehydrogenase complex

Yitang Zhang, Maofei Chen, Xudong Chen, Minghui Zhang, Jian Yin, Zi Yang, Xin Gao, Sensen Zhang () and Maojun Yang ()
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Yitang Zhang: Tsinghua University
Maofei Chen: Tsinghua University
Xudong Chen: Tsinghua University
Minghui Zhang: Shenzhen University Health Science Center
Jian Yin: Tsinghua University
Zi Yang: Tsinghua University
Xin Gao: King Abdullah University of Science and Technology (KAUST)
Sensen Zhang: Tsinghua University
Maojun Yang: Tsinghua University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The 2-oxoglutarate dehydrogenase complex (OGDHc) orchestrates a critical reaction regulating the TCA cycle. Although the structure of each OGDHc subunit has been solved, the architecture of the intact complex and inter-subunit interactions still remain unknown. Here we report the assembly of native, intact OGDHc from Sus scrofa heart tissue using cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET), and subtomogram averaging (STA) to discern native structures of the whole complex and each subunit. Our cryo-EM analyses revealed the E2o cubic core structure comprising eight homotrimers at 3.3-Å resolution. More importantly, the numbers, positions and orientations of each OGDHc subunit were determined by cryo-ET and the STA structures of the core were resolved at 7.9-Å with the peripheral subunits reaching nanometer resolution. Although the distribution of the peripheral subunits E1o and E3 vary among complexes, they demonstrate a certain regularity within the position and orientation. Moreover, we analyzed and validated the interactions between each subunit, and determined the flexible binding mode for E1o, E2o and E3, resulting in a proposed model of Sus scrofa OGDHc. Together, our results reveal distinctive factors driving the architecture of the intact, native OGDHc.

Date: 2024
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DOI: 10.1038/s41467-024-52792-7

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