ChemoproteomicProfiling of Lysine AcetyltransferasesHighlights an Expanded Landscape of Catalytic Acetylation
Lysine acetyltransferases (KATs)play a critical role in the regulationof gene expression, metabolism, and other key cellular functions.One shortcoming of traditional KAT assays is their inability to studyKAT activity in complex settings, a limitation that hinders effortsat KAT discovery, characterization, and inhibitor development. Toaddress this challenge, here we describe a suite of cofactor-basedaffinity probes capable of profiling KAT activity in biological contexts.Conversion of KAT bisubstrate inhibitors to clickable photoaffinityprobes enables the selective covalent labeling of three phylogeneticallydistinct families of KAT enzymes. Cofactor-based affinity probes reporton KAT activity in cell lysates, where KATs exist as multiproteincomplexes. Chemical affinity purification and unbiased LC–MS/MSprofiling highlights an expanded landscape of orphan lysine acetyltransferasespresent in the human genome and provides insight into the global selectivityand sensitivity of CoA-based proteomic probes that will guide futureapplications. Chemoproteomic profiling provides a powerful methodto study the molecular interactions of KATs in native contexts andwill aid investigations into the role of KATs in cell state and disease.
[…] Amino acid sequences for canonical
and orphan lysine acetyltransferases were obtained from Uniprot. Accession
numbers are provided in Table S3 (). A pairwise alignment was generated using Clustal Omega, and a phylogenic tree was constructed using
the neighbor-joining method. All phylogenetic trees were displayed
in hyperbolic space using Hypertree, with branches of the tree designated
by different colors and labeled by name where appropriate. […]
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