Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Toward an Understanding Of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxo Acid Dehydrogenase Complexes

Version 1 : Received: 11 April 2021 / Approved: 13 April 2021 / Online: 13 April 2021 (10:19:30 CEST)

A peer-reviewed article of this Preprint also exists.

Nemeria, N.S.; Zhang, X.; Leandro, J.; Zhou, J.; Yang, L.; Houten, S.M.; Jordan, F. Toward an Understanding of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxoacid Dehydrogenase Complexes. Life 2021, 11, 407. Nemeria, N.S.; Zhang, X.; Leandro, J.; Zhou, J.; Yang, L.; Houten, S.M.; Jordan, F. Toward an Understanding of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxoacid Dehydrogenase Complexes. Life 2021, 11, 407.

Journal reference: Life 2021, 11, 407
DOI: 10.3390/life11050407

Abstract

The 2-oxoglutarate dehydrogenase complex (OGDHc) is a key enzyme in the TCA cycle and represents one of the major regulators of mitochondrial metabolism through NADH and reactive oxygen species levels. The OGDHc impacts cell metabolic and cell signaling pathways through the coupling of 2-oxoglutarate metabolism to gene transcription related to tumor cell proliferation and aging. DHTKD1 is a gene encoding 2-oxoadipate dehydrogenase (E1a), which functions in the L-lysine degradation pathway. The potentially damaging variants in DHTKD1 have been associated to the (neuro) pathogenesis of several diseases. Evidence was obtained for the formation of a hybrid complex between the OGDHc and E1a, suggesting a potential cross talk between the two metabolic pathways and raising fundamental questions about their assembly. Here we reviewed the recent findings and advances in understanding of protein-protein interactions in OGDHc and 2-oxoadipate dehydrogenase complex (OADHc), an understanding that will create a scaffold to help design approaches to mitigate the effects of diseases associated with dysfunction of the TCA cycle or lysine degradation. A combination of biochemical, biophysical and structural approaches such as chemical cross-linking MS and cryo-EM appears particularly promising to provide vital information for the assembly of 2-oxo acid dehydrogenase complexes, their function and regulation.

Subject Areas

neurodegeneration, glucose metabolism, enzyme catalysis, protein-protein interaction, hydrogen exchange mass spectrometry, protein cross-linking, protein assembly, molecular modeling

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