Coenzyme A binding sites induce proximal acylation across protein families

Lysine Nɛ-acylations, such as acetylation or succinylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is predominantly non-enzymatic, and only a specific subset of the proteome is acylated. Coenzyme A (CoA) can act as an acyl group carrier...

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Veröffentlicht in:Scientific reports Jg. 13; H. 1; S. 5029 - 14
Hauptverfasser: Carrico, Chris, Cruz, Andrew, Walter, Marius, Meyer, Jesse, Wehrfritz, Cameron, Shah, Samah, Wei, Lei, Schilling, Birgit, Verdin, Eric
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 28.03.2023
Nature Publishing Group
Nature Portfolio
Schlagworte:
631/114
631/114/2410
631/114/663
631/45
631/45/173
631/45/475
631/45/612
Acetylation
Acyl Coenzyme A - metabolism
Acylation
Binding Sites
Coenzyme A
Computer applications
Enoyl-CoA hydratase
Humanities and Social Sciences
Lysine
Lysine - metabolism
Mass spectrometry
Mass spectroscopy
Mitochondria
multidisciplinary
Post-translation
Protein families
Protein Processing, Post-Translational
Proteins
Proteomes
Science
Science (multidisciplinary)
Succinyl-CoA
ISSN:2045-2322, 2045-2322
Online-Zugang:Volltext
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Zusammenfassung:Lysine Nɛ-acylations, such as acetylation or succinylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is predominantly non-enzymatic, and only a specific subset of the proteome is acylated. Coenzyme A (CoA) can act as an acyl group carrier via a thioester bond, but what controls the acylation of mitochondrial lysines remains poorly understood. Using published datasets, here we found that proteins with a CoA-binding site are more likely to be acetylated, succinylated, and glutarylated. Using computational modeling, we show that lysine residues near the CoA-binding pocket are highly acylated compared to those farther away. We hypothesized that acyl-CoA binding enhances acylation of nearby lysine residues. To test this hypothesis, we co-incubated enoyl-CoA hydratase short chain 1 (ECHS1), a CoA-binding mitochondrial protein, with succinyl-CoA and CoA. Using mass spectrometry, we found that succinyl-CoA induced widespread lysine succinylation and that CoA competitively inhibited ECHS1 succinylation. CoA-induced inhibition at a particular lysine site correlated inversely with the distance between that lysine and the CoA-binding pocket. Our study indicated that CoA acts as a competitive inhibitor of ECHS1 succinylation by binding to the CoA-binding pocket. Together, this suggests that proximal acylation at CoA-binding sites is a primary mechanism for lysine acylation in the mitochondria.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-31900-5