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

Christian Tüting, Fotis L. Kyrilis, Johannes Müller, Marija Sorokina, Ioannis Skalidis, Farzad Hamdi, Yashar Sadian and Panagiotis L. Kastritis ()
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Christian Tüting: Martin Luther University Halle-Wittenberg
Fotis L. Kyrilis: Martin Luther University Halle-Wittenberg
Johannes Müller: Martin Luther University Halle-Wittenberg
Marija Sorokina: Martin Luther University Halle-Wittenberg
Ioannis Skalidis: 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

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27287-4

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