Probing the E1o-E2o and E1a-E2o Interactions in Binary Subcomplexes of the Human 2-Oxoglutarate Dehydrogenase and 2-Oxoadipate Dehydrogenase Complexes by Chemical Cross-Linking Mass Spectrometry and Molecular Dynamics Simulation

Autor:	Oliver Ozohanics, Xu Zhang, Natalia S. Nemeria, Attila Ambrus, Frank Jordan
Rok vydání:	2023
Předmět:	2-oxoglutarate dehydrogenase 2-oxoadipate dehydrogenase Organic Chemistry protein–protein interactions molecular dynamics simulations General Medicine Catalysis Computer Science Applications Inorganic Chemistry Physical and Theoretical Chemistry Molecular Biology chemical cross-linking mass spectrometry Spectroscopy dihydrolipoyl succinyltransferase
Zdroj:	International Journal of Molecular Sciences Volume 24 Issue 5 Pages: 4555
ISSN:	1422-0067
DOI:	10.3390/ijms24054555
Popis:	The human 2-oxoglutarate dehydrogenase complex (hOGDHc) is a key enzyme in the tricarboxylic acid cycle and is one of the main regulators of mitochondrial metabolism through NADH and reactive oxygen species levels. Evidence was obtained for formation of a hybrid complex between the hOGDHc and its homologue the 2-oxoadipate dehydrogenase complex (hOADHc) in the L-lysine metabolic pathway, suggesting a crosstalk between the two distinct pathways. Findings raised fundamental questions about the assembly of hE1a (2-oxoadipate-dependent E1 component) and hE1o (2-oxoglutarate-dependent E1) to the common hE2o core component. Here we report chemical cross-linking mass spectrometry (CL-MS) and molecular dynamics (MD) simulation analyses to understand assembly in binary subcomplexes. The CL-MS studies revealed the most prominent loci for hE1o-hE2o and hE1a-hE2o interactions and suggested different binding modes. The MD simulation studies led to the following conclusions: (i) The N-terminal regions in E1s are shielded by, but do not interact directly with hE2o. (ii) The hE2o linker region exhibits the highest number of H-bonds with the N-terminus and α/β1 helix of hE1o, yet with the interdomain linker and α/β1 helix of hE1a. (iii) The C-termini are involved in dynamic interactions in complexes, suggesting the presence of at least two conformations in solution.
Databáze:	OpenAIRE
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