MassIVE MSV000089448

Partial Public PXD033787

Coenzyme A binding sites induce proximal acylation across protein families

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Description

Lysine acylations, such as acetylation, succinylation, or glutarylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is predominantly non-enzymatic and only a specific subset of the proteome has been identified as acylated. Coenzyme A (CoA), a metabolite required in several metabolic pathways, can act as an acyl group carrier via a thioester bond. However, what controls the acylation of lysine residues in the mitochondria remains poorly understood. Using published datasets, we found that proteins with a CoA-binding site are more likely to be acetylated, succinylated, and glutarylated. Using computational modeling, we discovered that, in CoA-binding proteins, lysine residues near the CoA-binding pocket are more likely to be acylated than those far away from the CoA-binding pocket. We hypothesized that acyl-CoA binding enhances the acylation of nearby lysine residues. To experimentally test this hypothesis, we used enoyl-CoA hydratase short chain 1 (ECHS1), a mitochondrial protein with a CoA-binding pocket, and co-incubated ECHS1 with succinyl-CoA and CoA. Using mass spectrometry, we found that succinyl-CoA induced widespread lysine succinylation and that CoA competitively inhibited ECHS1 succinylation. In addition, CoA-induced inhibition at a particular lysine site was inversely correlated with the distance between this lysine residue and the CoA-binding pocket. This indicated that CoA acts as a competitive inhibitor of ECHS1 succinylation by binding to the CoA-binding pocket. Together, this study suggests proximal acylation at protein CoA-binding sites is a primary mechanism for lysine acylation in the mitochondria. [doi:10.25345/C51C1TK4G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Lysine acylation ; CoA-binding site ; Quantitative proteomics ; Succinylation ; Proximal acylation

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Principal Investigators:
(in alphabetical order) 		Birgit Schilling, Buck Institute, USA
Submitting User: JoannaBons
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