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Cryo-EM snapshots of a native lysate provide structural insights into a metabolon-embedded transacetylase reaction

Author

Listed:
  • Christian Tüting

    (Martin Luther University Halle-Wittenberg)

  • Fotis L. Kyrilis

    (Martin Luther University Halle-Wittenberg
    Martin Luther University Halle-Wittenberg)

  • Johannes Müller

    (Martin Luther University Halle-Wittenberg)

  • Marija Sorokina

    (Martin Luther University Halle-Wittenberg
    RGCC International GmbH
    BioSolutions GmbH Weinbergweg 22)

  • Ioannis Skalidis

    (Martin Luther University Halle-Wittenberg
    Martin Luther University Halle-Wittenberg)

  • Farzad Hamdi

    (Martin Luther University Halle-Wittenberg)

  • Yashar Sadian

    (Université de Genève, Sciences II)

  • Panagiotis L. Kastritis

    (Martin Luther University Halle-Wittenberg
    Martin Luther University Halle-Wittenberg
    Biozentrum, Martin Luther University Halle-Wittenberg)

Abstract

Found across all kingdoms of life, 2-keto acid dehydrogenase complexes possess prominent metabolic roles and form major regulatory sites. Although their component structures are known, their higher-order organization is highly heterogeneous, not only across species or tissues but also even within a single cell. Here, we report a cryo-EM structure of the fully active Chaetomium thermophilum pyruvate dehydrogenase complex (PDHc) core scaffold at 3.85 Å resolution (FSC = 0.143) from native cell extracts. By combining cryo-EM with macromolecular docking and molecular dynamics simulations, we resolve all PDHc core scaffold interfaces and dissect the residing transacetylase reaction. Electrostatics attract the lipoyl domain to the transacetylase active site and stabilize the coenzyme A, while apolar interactions position the lipoate in its binding cleft. Our results have direct implications on the structural determinants of the transacetylase reaction and the role of flexible regions in the context of the overall 10 MDa PDHc metabolon architecture.

Suggested Citation

  • Christian Tüting & Fotis L. Kyrilis & Johannes Müller & Marija Sorokina & Ioannis Skalidis & Farzad Hamdi & Yashar Sadian & Panagiotis L. Kastritis, 2021. "Cryo-EM snapshots of a native lysate provide structural insights into a metabolon-embedded transacetylase reaction," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27287-4
    DOI: 10.1038/s41467-021-27287-4
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    References listed on IDEAS

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    1. B. O. Forsberg & S. Aibara & R. J. Howard & N. Mortezaei & E. Lindahl, 2020. "Arrangement and symmetry of the fungal E3BP-containing core of the pyruvate dehydrogenase complex," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Jana Škerlová & Jens Berndtsson & Hendrik Nolte & Martin Ott & Pål Stenmark, 2021. "Structure of the native pyruvate dehydrogenase complex reveals the mechanism of substrate insertion," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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