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PreprintCited by 29Biochemical Acid Research StudiesEnzyme Structure and FunctionAdvanced Electron Microscopy Techniques and Applications

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Structures and comparison of endogenous 2-oxoglutarate and pyruvate dehydrogenase complexes from bovine kidney

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Liu, Shiheng, Xia, Xian, Zhen, James, Li, Zihang, Zhou, Z. Hong·2022·Cell Discovery
DOI 10.1101/2022.04.06.487412PMC PMC9681731

Preprint — published as 10.1038/s41421-022-00487-y · Paper page

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Abstract

The α-keto acid dehydrogenase complex family catalyzes the essential oxidative decarboxylation of α-keto acids to yield acyl-CoA and NADH. Despite performing the same overarching reaction, members of the family have different component structures and structural organization between each other and across phylogenetic species. While native structures of α-keto acid dehydrogenase complexes from bacteria and fungi became available recently, the atomic structure and organization of their mammalian counterparts in their native states remain unknown. Here, we report the cryo electron microscopy (cryoEM) structures of the endogenous cubic 2-oxoglutarate dehydrogenase complex (OGDC) and icosahedral pyruvate dehydrogenase complex (PDC) cores from bovine kidney determined at 3.5 Å and 3.8 Å resolution, respectively. The structures of multiple protein were reconstructed from a single lysate sample, allowing direct structural comparison without the concerns of differences arising from sample preparation and structure determination. Although native and recombinant E2 core scaffold structures are similar, native structures are decorated with their peripheral E1 and E3 subunits. Asymmetric sub-particle reconstructions support heterogeneity in the arrangements of these peripheral subunits. Additionally, despite sharing a similar monomeric fold, OGDC and PDC E2 cores have distinct interdomain and intertrimer interactions, which suggests a means of modulating self-assembly to mitigate heterologous binding between mismatched E2 species. The lipoyl moiety lies near a mobile gatekeeper within the interdomain active site of OGDC E2 and PDC E2. Analysis of the two-fold related intertrimer interface identified secondary structural differences and chemical interactions between icosahedral and cubic geometries of the core. Taken together, our study provides direct structural comparison of OGDC and PDC from the same source and offers new insights into determinants of interdomain interactions and of architecture diversity among α-keto acid dehydrogenase complexes.

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Metadata

Authors
Liu, S., Xia, X., Zhen, J., Li, Z., & Zhou, Z. H.
Affiliations
California NanoSystems Institute (US)
Corresponding author
Zhou, Z. Hong
ORCID
Venue
Cell Discovery
Publisher
openRxiv
Published
2022-04-07
Volume
8
Issue
1
Pages
126-126
ISSN
2056-5968 (ISSN-L)
DOI
10.1101/2022.04.06.487412
PMC
PMC9681731
OpenAlex
W4309646950
Cited by
29
References
1
Citations by year
2026: 7 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 1
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cell Discovery (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Science Foundation (1338135, U24GM116792, 1548924)
  • U.S. Department of Health and Human Services (5T32AI060567, R01GM071940)
  • National Institutes of Health (1s10od018111-01)
  • National Institute of General Medical Sciences (U24GM116792, R01GM071940)
  • National Institute of Allergy and Infectious Diseases (T32AI060567)
  • Division of Materials Research (DMR1548924, 1548924)
  • National Center for Research Resources (S10RR023057)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
Keywords
2-oxoglutarate dehydrogenase, pyruvate dehydrogenase complex, bovine kidney, cryo-EM structure, domain-domain interactions, self-assembly, oxidative decarboxylation

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